Bi-functional compounds and methods for targeted ubiquitination of androgen receptor

ABSTRACT

The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitinization of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and/or otherwise inhibited by the compounds as described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application under 35 U.S.C.111(a), which claims priority to, and the benefit of, U.S. patentapplication Ser. No. 16/777,294, filed on Jan. 30, 2020, which claimspriority to, and the benefit of, U.S. Provisional Application No.62/798,554, filed on Jan. 30, 2019, the contents of each of which arehereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to therapeutic compounds and compositions, andmethods for their use in the treatment of various indications, includingvarious cancers. In particular, the invention relates to therapies andmethods of treatment for cancers such as prostate cancer.

BACKGROUND OF THE INVENTION

Prostate cancer is the most commonly diagnosed malignancy in males inthe United States and the second leading cause of male cancer mortality.Numerous studies have shown that the androgen receptor (AR) is centralnot only to the development of prostate cancer, but also the progressionof the disease to the castration resistance state (Taplin, M. E. et al.,J. Clin. Oncol. 2003 21:2673-8; and Tilley, W. D. et al., Cancer Res.1994 54:4096-4102). Thus, effective inhibition of human AR remains oneof the most effective therapeutic approaches to the treatment ofadvanced, metastatic prostate cancer.

Androgens are also known to play a role in female cancers. One exampleis ovarian cancer where elevated levels of androgens are associated withan increased risk of developing ovarian cancer (Helzlsouer, K. J. etal., JAMA 1995 274, 1926-1930; Edmondson, R. J. et al., Br. J. Cancer2002 86, 879-885). Moreover, AR has been detected in a majority ofovarian cancers (Risch, H. A., J. Natl. Cancer Inst. 1998 90, 1774-1786;Rao, B. R. et al., Endocr. Rev. 1991 12, 14-26; Clinton, G. M. et al.,Crit. Rev. Oncol. Hematol. 1997 25, 1-9).

AR belongs to the nuclear hormone receptor family that is activated byandrogens such as testosterone and dihydrotestosterone. These androgens,as well as antagonists such as enzalutamide, compete with the androgensthat bind to the ligand binding domain (LBD). AR possesses a modularorganization characteristic of all nuclear receptors. It is comprised ofan N-terminal domain (NTD), a central DNA binding domain (DBD), a shorthinge region, and C-terminal domain that contains a hormone ligandbinding pocket (the LBD, which also comprises the hormone binding site(HBS)) and the Activation Function-2 (AF2) site (Gao, W. Q. et al.,Chem. Rev. 2005 105:3352-3370). The latter represents a hydrophobicgroove on the AR surface which is flanked with regions of positive andnegative charges—“charge clamps” that are significant for binding ARactivation factors (Zhou, X. E. et al., J. Biol. Chem. 2010285:9161-9171).

The activation of AR follows a well characterized pathway: in thecytoplasm, the receptor is associated with chaperone proteins thatmaintain agonist binding conformation of the AR (Georget, V. et al.,Biochemistry 2002 41:11824-11831). Upon binding of an androgen, the ARundergoes a series of conformational changes, disassociation fromchaperones, dimerization, and translocation into the nucleus (Fang, Y.F. et al., J. Biol. Chem. 1996 271:28697-28702; and Wong, C. I. et al.,J. Biol. Chem. 1993 268:19004-19012) where it further interacts withco-activator proteins at the AF2 site (Zhou, X. E. et al. J. Biol. Chem.2010 285:9161-9171). This event triggers the recruitment of RNApolymerase II and other factors to form a functional transcriptionalcomplex with the AR.

In castration-resistant prostate cancer (CRPC), drug resistance canmanifest through AR-LBD mutations that convert AR-antagonists intoagonists or by expression of AR-variants lacking the LBD. AR is a majordriver of prostate cancer and inhibition of its transcriptional activityusing competitive antagonists such as enzalutamide and apalutamideremains a frontline therapy for prostate cancer management. Anothertherapy is abiraterone which is an inhibitor of cytochrome P450 17A1that impairs AR signaling by depleting adrenal and intratumoraltestosterone and dihydrotestosterone. Recent work (Antonarakis, E. S. etal., New Engl. J. Med. 2014 37, 1028-1038) has shown that patients onenzalutamide and abiraterone with a splice variant of AR, labelled asAR-V7, had lower PSA response rates, shorter PSA progression-freesurvival, and shorter overall survival.

AR-V7 lacks the LBD, which is the target of enzalutamide andtestosterone, but AR-V7 remains constitutively active as a transcriptionfactor. Accordingly, it is desirable to investigate other approaches toantagonize the AR receptor as well as AR-V7. The common domain betweenthese two proteins is the DBD and compounds have been identified asdiscussed in Li, H. et al., J. Med. Chem. 2014 57, 6458-6467 (2014);Dalal, K. et al., Mol. Cancer Ther. 2017 vol. 16, 2281-2291; Xu, R. etal., Chem. Biol. & Drug Design 2018 91(1), 172-180; and WO 2015/120543.

Several methods are available for the manipulation of protein levels,including bi-functional proteolysis targeting chimeric molecules(PROTACs) which contain a ligand that recognizes the target protein thatis linked to a ligand that binds to a specific E3 ubiquitin ligase. Theensuing bifunctional molecule binds to the target protein and the E3ligase enabling the transfer of ubiquitin to the target protein from theLigase provided there is a suitable acceptor on the target protein.Another method is the “molecular glue” process whereby the moleculetogether with the E3 ligase recruit the target protein to the E3 ligasefollowed by the ubiquitin transfer and degradation of the target(Chopra, R., Sadok, A., Collins, I., Drug Disc Today: Technologies,2019, 31, 5-13.) In the case of a compound acting as a “molecular glue”,the only requirement is the presence of an E3 ligase binding moiety.After binding to the E3 ligase, the ensuing moiety could recruit theprotein to be degraded. The labelling of proteins with ubiquitin isimplicated in the protein's turnover by the 26S proteasome.

Protein ubiquitination is a multi-step process whereby a ubiquitinprotein is successively relayed between different classes of enzymes(E1, E2, E3) in order to eventually tag a cellular substrate. Initially,the C-terminal carboxylate of ubiquitin is adenylated by the E1activating enzyme in an ATP-dependent step. Subsequently, a conservednucleophilic cysteine residue of the E1 enzyme displaces the AMP fromthe ubiquitin adenylate resulting in a covalent ubiquitin thioesterconjugate. The binding and ensuing adenylation of a second ubiquitinmolecule promote the recruitment of an E2 conjugating enzyme to thisternary complex. An active site Cys on the E2 subsequently facilitatesthe transfer of the covalently linked ubiquitin from the E1 to a Cysresidue on the E2 through a trans-thioesterification reaction.Concomitantly, an E3 ligase recruits a specific downstream targetprotein and mediates the transfer of the ubiquitin from the E2 enzyme tothe terminal substrate through either a covalent or non-covalentmechanism. Each ubiquitin is ligated to a protein through either apeptide bond with the N-terminal amino group or an isopeptide bondformed between a side chain F-amino group of a select Lys residue on thetarget protein and the ubiquitin.

Deubiquitinating enzymes (DUBs) are enzymes that specifically cleave theubiquitin protein from the substrate thereby offering additionalmechanisms of regulation over the entire labeling pathway. In thecurrent human proteome there are eight known human E1s, about 40 E2s,over 600 E3s and over 100 DUBs. These enzymes are well described inPavia, S. et al., J. Med. Chem. 2018 61(2), 405-421.

The E3 ligases originate in three major classes—the RING finger andU-box E3s, the HECT E3s, and the RING/HECT-hybrid type E3s. The E3ligases are localized in various cell organelles and hence theeffectiveness of the E3 ligase ligand depends at least in part on thelocation of the protein targeted for degradation, assuming that the fullmolecule is available within the appropriate location in the cell. Inaddition, for every combination of the target ligand and the ubiquitinrecruiting ligand, the linker length and conformational flexibility alsocontributes to the effectiveness of the degradation molecule. Themechanism depends on the availability of a Lys residue on the surface ofthe protein close to the targeted protein ligand binding pocket.Ubiquitin binds at Lys residues and hence the “delivery” of ubiquitinfor binding at the appropriate Lys influences the effectiveness of thedegradation molecule. Crew et al. (US20170327469A1, US20180099940A1) areprogressing a proposed treatment for castration-resistant prostatecancer based on bifunctional molecules coupling various E3 ligases to ARantagonists binding at the AR LBD site. Our approach is different inthat we do not target the LBD site but the DBD site and,correspondingly, the chemical matter is quite different.

There exists a continuing need for effective treatments for diseases andconditions that are related to aberrant AR regulation or activity, forexample, cancers such as prostate cancer, and Kennedy's Disease. Indeveloping such treatments, it would be desirable to have a moleculewhich can simultaneously bind AR and an E3 ubiquitin ligase and whichalso promotes ubiquitination of AR-V7 and perhaps AR, and leads todegradation of AR-V7 and AR by the proteasome.

SUMMARY OF THE INVENTION

The present invention relates to bi-functional compounds which functionto recruit endogenous proteins to an E3 ubiquitin ligase fordegradation, and methods for using same. More specifically, the presentdisclosure provides specific proteolysis targeting chimera (PROTAC)molecules which find utility as modulators of targeted ubiquitinizationof a variety of polypeptides and other proteins, such as AR, which arethen degraded and/or otherwise inhibited by the compounds as describedherein.

In one aspect, these PROTAC molecules comprise an E3 ubiquitin ligasebinding moiety (i.e., a ligand for an E3 ubiquitin ligase) linked to amoiety that binds a target protein (i.e., a protein/polypeptidetargeting ligand) such that the target protein/polypeptide is placed inproximity to the ubiquitin ligase to effect degradation (and/orinhibition) of that protein. In addition, the description providesmethods for using an effective amount of the compounds described hereinfor the treatment or amelioration of a disease condition includingcancer, e.g., prostate cancer, and Kennedy's Disease.

Suitable ligands that bind to the E3 ubiquitin ligase include cereblonbinders such as immunomodulatory imide drugs (IMiDs) includingthalidomide, pomalidomide, and lenalidomide (Deshales, R. J., NatureChem Biol. 2015 11, 634-635), and analogs or derivatives thereof. TheIMiDs themselves act as “molecular glues” and therefore have been shownto recruit a different set of proteins for degradation (reference). Inaddition, we have uncovered an intermediate molecule that acts via the“molecular glue” mechanism. Other suitable E3 ubiquitin ligase bindersare E3 CRL2^(VHL) compounds, also called Von-Hippel-Lindau or VHLligands, the cellular inhibitor of apoptosis protein (IAP) as discussedin Shibata, N. et al., J. Med. Chem., 2018 61(2), 543-575. Binders ofthe E3 ligase Mouse Double Minute 2 (MDM2) comprise the fourth class ofE3 Ligase Binders (E3LBs) that are utilized (Skalniak, L., et al.,Expert Opin. Ther, Patents, 2019, 29, 151-170).

In one aspect, there are provided compositions comprising such compoundswhich function to recruit proteins including AR-V7 and AR for targetedubiquitination and degradation. In some embodiments, the structure ofsuch compounds can be depicted as:

ARB-E3LB

wherein ARB is an AR binding moiety and E3LB is a ubiquitin ligasebinding moiety.

In some embodiments, the compounds may further comprise a chemicallinker (“L”). The structure of such compounds can be depicted as:

ARB-L-E3LB

wherein ARB is an AR binding moiety, L is a bond or linker moiety, andE3LB is a ubiquitin ligase binding moiety.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or pharmaceutically acceptable salt form thereof, and apharmaceutically acceptable carrier. The therapeutic compositionsmodulate protein degradation in a patient or subject, for example, ananimal such as a human, and can be used for treating or amelioratingdisease states or conditions which are modulated through the degradedprotein. In certain embodiments, the therapeutic compositions asdescribed herein may be used to effectuate the degradation and/orinhibition of proteins of interest for the treatment or amelioration ofa disease, e.g., cancer.

In another aspect, the present disclosure provides a method ofubiquitinating/degrading a target protein in a cell. In certainembodiments, the method comprises administering a bi-functional compoundas described herein comprising an ARB moiety and a E3LB moiety,preferably linked through a linker moiety, as otherwise describedherein, wherein the E3LB moiety is coupled to the ARB moiety and whereinthe E3LB moiety recognizes an E3 ubiquitin ligase and the ARB moietyrecognizes the target protein such that degradation of the targetprotein occurs when the target protein is placed in proximity to theubiquitin ligase, thus resulting in degradation/inhibition of theeffects of the target protein and the control of protein levels. Thecontrol of protein levels afforded by the present disclosure providestreatment of a disease state or condition, which is modulated throughthe target protein by lowering the level of that protein in the cells ofa patient.

In another aspect, the description provides methods for treating orameliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a pharmaceutical composition comprising aneffective amount, e.g., a therapeutically effective amount, of acompound as described herein or pharmaceutically acceptable salt formthereof, and a pharmaceutically acceptable carrier, wherein thecomposition is effective for treating or ameliorating the disease ordisorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

The preceding general areas of utility are given by way of example onlyand are not intended to be limiting on the scope of the presentdisclosure and appended claims. Additional objects and advantagesassociated with the compositions, methods, and processes of the presentdisclosure will be appreciated by one of ordinary skill in the art inlight of the instant claims, description, and examples. For example, thevarious aspects and embodiments of the invention may be utilized innumerous combinations, all of which are expressly contemplated by thepresent description. These additional advantages objects and embodimentsare expressly included within the scope of the present disclosure. Thepublications and other materials used herein to illuminate thebackground of the invention, and in particular cases, to provideadditional details respecting the practice, are incorporated byreference. Where applicable or not specifically disclaimed, any one ofthe embodiments described herein are contemplated to be able to combinewith any other one or more embodiments, even though the embodiments aredescribed under different aspects of the disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an immunoblot of certain exemplified compounds.

DETAILED DESCRIPTION

The following is a detailed description provided to aid those skilled inthe art in practicing the present invention. Those of ordinary skill inthe art may make modifications and variations in the embodimentsdescribed herein without departing from the spirit or scope of thepresent disclosure. All publications, patent applications, patents,figures and other references mentioned herein are expressly incorporatedby reference in their entirety.

The present description relates to the surprising and unexpecteddiscovery that an E3 ubiquitin ligase protein can ubiquitinate a targetprotein, in particular the androgen receptor of a slice variant of ARwhich lacks the LBD, labelled as AR-V7, once the E3 ubiquitin ligaseprotein and the target protein are brought into proximity by a chimericconstruct (e.g., a PROTAC) as described herein, in which a moiety thatbinds the E3 ubiquitin ligase protein is coupled, e.g., covalently, to amoiety that binds the androgen receptor target protein. Accordingly, thepresent description provides compounds, compositions comprising thesame, and associated methods of use for ubiquitination and degradationof a chosen target protein, e.g., androgen receptor AR-V7.

In one aspect, the present disclosure provides compounds useful forregulating protein activity. The composition comprises a ubiquitinpathway protein binding moiety (preferably for an E3 ubiquitin ligase,alone or in complex with an E2 ubiquitin conjugating enzyme which isresponsible for the transfer of ubiquitin to targeted proteins)according to a defined chemical structure and a protein targeting moietywhich are linked or coupled together, preferably through a linker,wherein the ubiquitin pathway protein binding moiety recognizes aubiquitin pathway protein and the targeting moiety recognizes a targetprotein (e.g., androgen receptor). Such compounds may be referred toherein as PROTAC compounds or PROTACs.

In one aspect, the PROTACs of the present invention comprise an E3ubiquitin ligase binding moiety (“E3LB”), and a moiety that binds atarget protein (i.e. a protein/polypeptide targeting ligand) that is anAR binding moiety (“ARB”). In this embodiment, the structure of thebi-functional compound can be depicted as:

ARB-E3LB

where ARB is an AR binding moiety as described herein, and E3LB is an E3ligase binding moiety as described herein

In certain embodiments the bi-functional compound further comprises achemical linker (“L”). In these embodiments, the structure of thebi-functional compounds can be depicted as:

ARB-L-E3LB

where ARB is an AR binding moiety as described herein, E3LB is an E3ligase binding moiety as described herein, and L is a chemical linkermoiety, e.g., a linker as described herein, or optionally a bond, thatlinks the ARB and E3LB moieties.

The respective positions of the ARB and E3LB moieties as well as theirnumber as illustrated herein is provided by way of example only and isnot intended to limit the compounds in any way. As would be understoodby the skilled artisan, the bi-functional compounds as described hereincan be synthesized such that the number and position of the respectivefunctional moieties can be varied as desired. In certain embodiments,the compounds as described herein comprise multiple E3LB moieties,multiple ARB moieties, multiple chemical linkers, or a combinationthereof.

It will be understood that the general structures are exemplary and therespective moieties can be arranged spatially in any desired order orconfiguration, e.g., ARB-L-E3LB, and E3LB-L-ARB, respectively. The E3LBgroup and ARB group may be covalently linked to the linker group throughany covalent bond which is appropriate and stable to the chemistry ofthe linker. It will be further understood that for all compoundsdescribed herein, one or more hydrogen atoms may be replaced with anequivalent number of deuterium atoms.

In certain embodiments, the ARB may be selected from the followingstructures:

wherein L is the linker in the general formula above;

A is 3-7 membered alicyclic with 0-4 heteroatoms or aryl, heteroarylindependently substituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH,NR²R³, OCH₃, OC₁₋₃ alkyl (optionally substituted by 1 or more halo),CH₂F, CHF₂, CF₃, C₁₋₆ alkyl (linear, branched, optionally substituted by1 or more halo, C₁₋₆ alkoxyl), C₁₋₆ alkoxyl (linear, branched,optionally substituted by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl,3-6 membered alicyclic with 0-4 heteroatoms and substituted by 1 or morehalo, hydroxyl, nitro, CN, C≡CH, CF₃, C₁₋₆ alkyl (linear, branched,optionally substituted by 1 or more halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy(linear, branched, optionally substituted by 1 or more halo), C₂₋₆alkenyl, or C₂₋₆ alkynyl;

B is aryl, heteroaryl independently substituted by 1 or more halo,hydroxyl, nitro, CN, C≡CH, NR²R³, OCH₃, OC₁₋₃ alkyl (optionallysubstituted by 1 or more halo), CF₃, C₁₋₆ alkyl (linear, branched,optionally substituted by 1 or more halo, C₁₋₆ alkoxyl), C₁₋₆ alkoxyl(linear, branched, optionally substituted by 1 or more halo), C₂₋₆alkenyl, C₂₋₆ alkynyl, 3-6 membered alicyclic with 0-4 heteroatoms andsubstituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, CF₃, C₁₋₆alkyl (linear, branched, optionally substituted by 1 or more halo, C₁₋₆alkoxy), C₁₋₆ alkoxy (linear, branched, optionally substituted by 1 ormore halo), C₂₋₆ alkenyl, or C₂₋₆ alkynyl, wherein the linker L isattached to B; and

R¹ are independently H, OH, CONH₂, CONR²R³, SONH₂, SONR²R³, SO₂NH₂,SO₂NR²R³, NHCO C₁₋₃ alkyl (optionally substituted by 1 or more halo),NR²COC₁₋₃ alkyl (optionally substituted by 1 or more halo), NR²SO₂C₁₋₃alkyl (optionally substituted by 1 or more halo), NR²SOC₁₋₃ alkyl(optionally substituted by 1 or more halo), CN, C≡CH, NH₂, NR²R³, OCH₃,OC₁₋₃ alkyl (optionally substituted by 1 or more halo), CHF₂, CH₂F, CF₃,halo, C₁₋₆ alkyl (linear, branched, optionally substituted by 1 or morehalo, C₁₋₆ alkoxyl) or, if applicable, taken together with an R¹ on anadjacent bonded atom, together with the atoms they are attached to, forma 3-6 membered ring alicyclic, aryl, or heteroaryl system containing 0-2heteroatoms, and R², R³ is independently H, halo, C₁₋₆ alkyl (optionallysubstituted by 1 or more F) or taken together with the atom they areattached to, form a 3-8 membered ring system containing 0-2 heteroatoms.

In one aspect, A is:

wherein R¹ is described above.

In another aspect, A is: R

wherein R¹ is described above and X=C or N.

In yet another aspect, B is: R

wherein L is the linker as described above, and R¹ is described above.

In still another aspect, B is:

wherein L is the linker as described above, and R¹ is described above.

In yet another aspect, B is:

wherein L is the linker as described above, and R¹ is described above.

The linker group (L) comprises a chemical structural unit represented bythe formula: -A_(q)-, in which q is an integer greater than 1; and A isindependently selected from the group consisting of a bond,CR^(L1)R^(L2), O, S, SO, SO₂, NR^(L3) SO₂NR^(L3), SONR^(L3), CONR^(L3),NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO, CR^(L1)═CR^(L2), C≡C,SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1), NR^(L3)C(═NCN)NR^(L4),NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4), C₃₋₁₁ cycloaklyl optionallysubstituted with 0-6 R^(L1) and/or R^(L2) groups, and heteroaryloptionally substituted with 0-6 R^(L1) and/or R^(L2) groups, whereinR^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are each independentlyselected from the group consisting of H, halo, C₁₋₈ alkyl, OC₁₋₈ alkyl,SC₁₋₈ alkyl, NHC₁₋₈ alkyl, N(C₁₋₈ alkyl)₂, C₃₋₁₁ cycloalkyl, aryl,heteroaryl, C₃₋₁₁ heterocyclyl, OC₁₋₈ cycloalkyl, SC₁₋₈ cycloalkyl,NHC₁₋₈ cycloalkyl, N(C₁₋₈cycloalkyl)₂, N(C₁₋₈ cycloalkyl)(C₁₋₈ alkyl),OH, NH₂, SH, SO₂C₁₋₈ alkyl, P(O)(OC₁₋₈ alkyl)(C₁₋₈ alkyl), P(O)(OC₁₋₈alkyl)₂, CC—C₁₋₈ alkyl, CCH, CH═CH(C₁₋₈ alkyl), C(C₁₋₈ alkyl)═CH(C₁₋₈alkyl), C(C₁₋₈ alkyl)═C(C₁₋₈ alkyl)₂, Si(OH)₃, SiC(₁₋₈ alkyl)₃,Si(OH)(C₁₋₈ alkyl)₂, COC₁₋₈ alkyl, CO₂H, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅,SO₂NHC₁₋₈ alkyl, SO₂NHC₁₋₈ alkyl, SO₂N(C₁₋₈ alkyl)₂, SONHC₁₋₈ alkyl,SON(C₁₋₈ alkyl)₂, CONHC₁₋₈ alkyl, CON(C₁₋₈ alkyl)₂, N(C₁₋₈alkyl)CONH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)CON(C₁₋₈ alkyl)₂, NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈ alkyl)₂, NHCONH₂, N(C₁₋₈ alkyl)SO₂NH(C₁₋₈ alkyl),N(C₁₋₈ alkyl)SO₂N(C₁₋₈ alkyl)₂, NHSO₂NH(C₁₋₈ alkyl), NHSO₂N(C₁₋₈ alkyl)₂and NHSO₂NH₂. R^(L1) and R^(L2) each, independently can be linked toanother A group to form a cycloalklyl and or heterocyclyl moiety thatcan be further substituted with 0-4 R^(L5) groups.

In certain embodiments, the E3LB moiety may be selected from a varietyof moieties, including the following structures:

wherein “

” in the above structures, represents a bond that may be stereospecific((R) or (S)), or non-stereospecific;

R¹ is described above;

R⁴ is selected from H, alkyl (linear, branched, optionally substitutedwith R⁵), OH, R⁵OCOOR⁶, R⁵OCONR⁵R⁷, CH₂-heterocyclyl optionallysubstituted with R⁵, or benzyl optionally substituted with R⁵;

R⁵ and R⁷ are each independently a bond, H, alkyl (linear, branched),cycloalkyl, aryl, hetaryl heterocyclyl, or —C(═O)R⁶ each of which isoptionally substituted; and

R⁶ is selected from CONR⁵R⁷, OR⁵, NR⁵R⁷, SR⁵, SO₂R⁵, SO₂NR⁵R⁷, CR⁵R⁷,CR⁵NR⁵R⁷, aryl, hetaryl, alkyl (linear, branched, optionallysubstituted), cycloalkyl, heterocyclyl, P(O)(OR⁵)R⁷, P(O)R⁵R⁷,OP(O)(OR⁵)R⁷, OP(O)R⁵R⁷, Cl, F, Br, I, CF₃, CHF₂, CH₂F, CN, NR⁵SO₂NR⁵R⁷,NR⁵CONR⁵R⁷, CONR⁵COR⁷, NR⁵C(═N═CN)NR⁵R⁷, C(═N—CN)NR⁵R⁷, NR⁵C(—N═CN)R⁷,NR⁵C(═C—NO₂)NR⁵R⁷, SO₂NR⁵COR⁷, NO₂, CO₂R⁵, C(C═N—OR⁵)R⁷, CR⁵, CR⁵R⁷,CCR⁵, S(C═O)(C═N—R⁵)R⁷, SF⁵, R⁵NR⁵R⁷, (R⁵O)_(n)R⁷, or OCF₃, where n isan integer from 1 to 10.

The E3LB moiety may also be selected from E3LB-e and E3LB-f as describedbelow:

wherein L is the linker previously described; R⁸ is H, a straight chainor branched C₁₋₈ alkyl, C₃₋₆ cycloalkyl, halo, CFH₂, CF₂H, or CF₃; andR⁹ is a H, halo, 4-methylthiazol-5-ylm, or oxazol-5-yl.

wherein L is the linker previously described and R¹¹ is independentlyoptionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted arylalkoxy, optionally substituted heteroaryl,optionally substituted heterocyclyl, optionally substitutedheterocyclyalkyl wherein the substituents are alkyl, halogen, or OH.

The E3LB moiety may also be selected from E3LB-g, E3LB-h, E3LB-i,E3LB-j, and E3LB-k as described below:

wherein L is the linker previously described;

R¹⁰ are independently optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted arylalkyl, optionally substituted aryl,optionally substituted thioalkyl wherein the substituents attached tothe S atom of the thioalkyl are optionally substituted alkyl, optionallysubstituted branched alkyl, optionally substituted heterocyclyl,(CH₂)_(v)COR¹⁴, CH₂CHR¹⁵COR¹⁶ or CH₂R¹⁷, where v=1 to 3; R¹⁴ and R¹⁶ areindependently selected from OH, NR¹⁸R¹⁹, or —OR²⁰; R¹⁵ is —NR¹⁸R¹⁹; R¹⁷is optionally substituted aryl or optionally substituted heterocyclyl,where the optional substituents include alkyl and halogen; R¹⁸ ishydrogen or optionally substituted alkyl; R¹⁹ is hydrogen, optionallysubstituted alkyl, optionally substituted branched alkyl, optionallysubstituted arylalkyl, optionally substituted heterocyclyl,—CH₂(OCH₂CH₂O)_(w)CH₃, or a polyamine chain, where w=1 to 8; andoptional substituents may be OH, halo, or NH₂;

R¹² and R¹³ are independently hydrogen, optionally substituted alkyl, oroptionally substituted cycloalkyl;

X is CH₂, N, or O; Y is S or O;

D is a bond (direct bond between X and L) or a ring which may be aryl,heteroaryl independently substituted by 1 or more halo, hydroxyl, nitro,CN, C═CH, NR²R³, OCH₃, OC₁₋₃ alkyl (optionally substituted by 1 or morehalo), CF₃, C₁₋₆ alkyl (linear, branched, optionally substituted by 1 ormore halo, C₁₋₆ alkoxyl), C₁₋₆ alkoxyl (linear, branched, optionallysubstituted by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-6 memberedalicyclic with 0-4 heteroatoms and substituted by 1 or more halo,hydroxyl, nitro, CN, C≡CH, CF₃, C₁₋₆ alkyl (linear, branched, optionallysubstituted by 1 or more halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy (linear,branched, optionally substituted by 1 or more halo), C₂₋₆ alkenyl, orC₂₋₆ alkynyl. R², R³ is independently H, halo, C₁₋₆ alkyl (optionallysubstituted by 1 or more F) or taken together with the atom they areattached to, form a 3-8 membered ring system containing 0-2 heteroatoms;and

R²⁰ is selected from the group consisting of:

wherein A is a C₄₋₈ aliphatic ring, and B is an aryl or N-containingheteroaryl and optionally substituted by alkyl or haloalkyl.

Optionally, E3LB may be selected from the MDM2 class of E3 ligasesrepresented by E3LB-1 below.

wherein R²² is independently aryl or heteroaryl optionally substitutedby halogen, mono-, di or tri-substituted halogen;

R²¹ is independently aryl or heteroaryl, optionally substituted bymono-, di- or tri-substituted halogen, CN, ethynyl, cyclopropyl, methyl,ethyl, isopropyl, methoxy, ethoxy, isopropoxy, other C₁₋₆ alkyl, otherC₁₋₆ alkenyl and C₁₋₆ alkynyl;

R²³ is selected from alkyl, substituted alkyl, alkenyl, substitutedalkenyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl andsubstituted cycloalkenyl;

R²⁴ is H, alkyl, aryl, substituted alkyl, cycloalkyl, aryl substitutedcycloalkyl and alkoxy substituted cycloalkyl; and

E is para-substituted aryl, single or multiple N containing heteroaryloptionally substituted by —OCH₃, —OCH₂CH₃ and halogen. L is the linkerpreviously defined above.

The E3LB moiety is inclusive of all cereblon binders such asimmunomodulatory imide drugs (IMiDs) including thalidomide,pomalidomide, and lenalidomide, and analogs or derivatives thereof, aswell as E3 CRL2^(1L) compounds, the cellular inhibitor of apoptosisprotein (IAP), and the mouse double minute 2 (MDM2) binders.

In certain embodiments, the compounds as described herein comprise aplurality of E3LB moieties and/or a plurality of ARB moieties. Incertain additional embodiments, the compounds as described hereincomprise multiple ARB moieties (targeting the same or differentlocations of the AR), multiple E3LB moieties, one or more moieties thatbind specifically to another E3 ubiquitin ligase, e.g., VHL, IAP, MDM2,or a combination thereof. In any of the aspects of embodiments describedherein, the ARB moieties, E3LB moieties, and other moieties that bindspecifically to another E3 ubiquitin ligase can be coupled directly orvia one or more chemical linkers or a combination thereof. In additionalembodiments, where a compound has multiple moieties that bindspecifically to another E3 ubiquitin ligase, the moieties can be for thesame E3 ubiquitin ligase or each respective moiety can bind specificallyto a different E3 ubiquitin ligase. In those embodiments where acompound has multiple ARB moieties, such moieties may be the same or,optionally, different.

In certain embodiments, where the compound comprises multiple EMLBmoieties, the EMLB moieties are identical or, optionally, different. Inadditional embodiments, the compound comprising a plurality of E3LBmoieties further comprises at least one ARB moiety coupled to a EMLBmoiety directly or via a chemical linker (“L”) or both. In certainadditional embodiments, the compound comprising a plurality of E3LBmoieties further comprises multiple ARB moieties. In still additionalembodiments, the ARB moieties are the same or, optionally, different.

In certain embodiments, the compound is selected from the groupconsisting of the exemplary compounds as described below, and salts andpolymorphs thereof:

Example 1

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(6-((2-(2,6-dioxopiperidin- 3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide Example 2

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(8-((2-(2,6-dioxopiperidin- 3-yl)-l,3-dioxoisoindolin-4-yl)amino)octyl)acetamide Example 3

2-(2,3-difluoro-6-(2-morpholinothiazol-4- yl)phenoxy)-N-(10-((2-(2,6-dioxopiperidin- 3-yl)-l,3-dioxoisoindolin-4- yl)amino)decyl)acetamideExample 4

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide Example 5

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl) acetamide Example 6

2-(2,3-difluoro-6-(2-morpholinothiazol-4- yl)phenoxy)-N-(14-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)acetamide Example 7

2-(2,3-difluoro-6-(2-morpholinothiazol-4- yl)phenoxy)-N-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)hexyl)acetamide Example 8

2-(2,3-difluoro-6-(2-morpholinothiazol-4- yl)phenoxy)-N-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)octyl)acetamide Example 9

2-(2,3-difluoro-6-(2-morpholinothiazol-4- yl)phenoxy)-N-(10-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)decyl)acetamide Example 10

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)ethoxy)ethyl) acetamide Example 11

2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(l-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3-azatetradecan-14- yl)acetamide Example 12

4-((2-(2-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione Example 13

4-((2-(2-(2-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl) isoindoline-l,3-dione Example 14

N-(14-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)acetamideExample 15

(2S,4R)-l-((S)-2-(4-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide Example 16

(2S,4R)-l-((S)-2-(5-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide Example 17

(2S,4R)-l-((S)-2-(6-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide Example 18

(2S,4R)-l-((S)-2-(7-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide Example 19

(2S,4R)-l-((S)-2-(2-(3-(2-(2,3-difluoro-6- (2-morpholinothiazol-4-yl)phenoxy)acetamido)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l- (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Example 20

(2S,4R)-l-((S)-2-(ter/-butyl)-14-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-4,13-dioxo-6,9-dioxa-3,12-diazatetradecanoyl)-4-hydroxy-N-((S)-l-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Example 21

(2S,4R)-l-((S)-2-(8-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)octanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide Example 22

(2S,4R)-N-((S)-3-((4-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-l-(4- (4-methylthiazol-5-yl)phenyl)-3-oxopropyl)- l-((S)-2-(1-fluorocyclopropane-l-carboxamido)-3,3-dimethylbutanoyl)-4- hydroxypyrrolidine-2-carboxamideExample 23

(2S,4R)-N-((S)-3-((6-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-l-(4- (4-methylthiazol-5-yl)phenyl)-3-oxopropyl)- l-((S)-2-(1-fluorocyclopropane-l-carboxamido)-3,3-dimethylbutanoyl)-4- hydroxypyrrolidine-2-carboxamideExample 24

(S)-l-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-((S)- l-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4- yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-l-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2- carboxamide Example 25

(S)-l-((S)-2-cyclohexyl-2-((S)-2- (methylamino)propanamido)acetyl)-N-((S)-l- ((4-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-l-oxo-3,3-diphenylpropan-2-yl)pyrrolidine- 2-carboxamide Example 26

(S)-l-((S)-2-cyclohexyl-2-((S)-2- (methylamino)propanamido)acetyl)-N-((S)-l- ((6-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-l-oxo-3,3-diphenylpropan-2-yl)pyrrolidine- 2-carboxamide Example 27

(2R,3S,4R,5S)-3-(3-chloro-2- fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((2-(2-(2-(2,3-difluoro-6-(2-morpholino-thiazol-4-yl)phenoxy)ethoxy)ethoxy) ethyl)carbamoyl)-2-methoxyphenyl)-5-neopentyl-pyrrolidine-2-carboxamide Example 28

(2R,3S,4R,5S)-3-(3-chloro-2- fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4- ((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2- carboxamide Example 29

(2R,3S,4R,5S)-3-(3-chloro-2- fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4- ((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2- carboxamide Example 30

N-(5-(((S)-l-((2S,4R)-4-hydroxy-2-(((S)-l- (4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-5-oxopentyl)-2-morpholinobenzo[d]thiazole- 4-carboxamide Example 31

N-(6-((S)-2-((S)-l-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl) pyrrolidin e-2-carboxamido)-3,3-diphenylpropanamido)hexyl)-2- morpholinobenzo[d]thiazole-4- carboxamideExample 32

N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-l-(2-morpholinothiazol-4-yl)-1H-imidazole-4- carboxamide Example 33

2,5-dibromo-N-(6-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-l-(2-morpholinothiazol-4-yl)-1H-imidazole- 4-carboxamide Example 34

4-((10-aminodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride Example 35

(S)-7-(2-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)-2-((S)-3,3- dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-l-yl)-l,2,3,4-tetrahydroisoquinoline-3- carboxamidedihydrochloride Example 36

(S)-7-(2-(2-(2-(2,3-difluoro-6-(2- morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)-2-((S)- 3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-l-yl)-l,2,3,4-tetrahydroisoquinoline-3- carboxamidedihydrochloride

In one aspect, the disclosure provides compounds of formula (I):

which is referred to as Androgen Receptor Binder-Linker-E3 Ligase Binder(I). It is understood that the terms “Androgen Receptor Binder,”“Androgen Receptor Binding Moiety” and “AR Binding Moiety” refer amolecular structure which generally binds successfully to androgenreceptor protein, recognizing that in different people androgenreceptors will not have the identical amino acid sequence, and thus, thestrength of binding may vary across different particular AR sequences.In further embodiments of this aspect, the present disclosure provides:

-   -   1.1 A compound having a chemical structure ARB-L-E3LB or        ARB-Link-E3LB, wherein ARB is an AR binding moiety that does not        bind to a ligand binding domain, E3LB is an E3 ligase binding        moiety, and L or Link is a linker coupling the AR binding moiety        to the E3 ligase binding moiety.    -   1.2 Compound 1.1, wherein the AR binding moiety binds to one        more of AR splice variants V1 to V15, for example, to AR splice        variant V7 (AR-V7).    -   1.3 Compound 1.1 or 1.2, wherein the AR binding moiety is        selected from:

-   -   -   wherein:            -   A is 3-7 membered alicyclic with 0-4 heteroatoms (e.g.,                morpholinyl) or aryl, heteroaryl independently                substituted by 1 or more halo, hydroxyl, nitro, CN,                C≡CH, NR²R³, OCH₃, OC₁₋₃ alkyl (optionally substituted                by 1 or more halo), CH₂F, CHF₂, CF₃, C₁₋₆ alkyl (linear,                branched, optionally substituted by 1 or more halo, C₁₋₆                alkoxyl), C₁₋₆ alkoxyl (linear, branched, optionally                substituted by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆                alkynyl, 3-6 membered alicyclic with 0-4 heteroatoms and                substituted by 1 or more halo, hydroxyl, nitro, CN,                C≡CH, CF₃, C₁₋₆ alkyl (linear, branched, optionally                substituted by 1 or more halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy                (linear, branched, optionally substituted by 1 or more                halo), C₂₋₆ alkenyl, or C₂₋₆ alkynyl;            -   B is aryl (e.g., phenyl), heteroaryl (e.g., imidazolyl)                independently substituted by 1 or more halo, hydroxyl,                nitro, CN, C≡CH, NR²R³, OCH₃, OC₁₋₃ alkyl (optionally                substituted by 1 or more halo), CF₃, C₁₋₆ alkyl (linear,                branched, optionally substituted by 1 or more halo, C₁₋₆                alkoxyl), C₁₋₆ alkoxyl (linear, branched, optionally                substituted by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆                alkynyl, 3-6 membered alicyclic with 0-4 heteroatoms and                substituted by 1 or more halo, hydroxyl, nitro, CN,                C≡CH, CF₃, C₁₋₆ alkyl (linear, branched, optionally                substituted by 1 or more halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy                (linear, branched, optionally substituted by 1 or more                halo), C₂₋₆ alkenyl, or C₂₋₆ alkynyl, wherein the linker                L is attached to B; and            -   R¹ is each independently H, OH, CONH₂, CONR²R³, SONH₂,                SONR²R³, SO₂NH₂, SO₂NR²R³, NHCO—C₁₋₃ alkyl (optionally                substituted by 1 or more halo), NR²COC₁₋₃ alkyl                (optionally substituted by 1 or more halo), NR²SO₂C₁₋₃                alkyl (optionally substituted by 1 or more halo),                NR²SOC₁₋₃ alkyl (optionally substituted by 1 or more                halo), CN, C═CH, NH₂, NR²R³, OCH₃, OC₁₋₃ alkyl                (optionally substituted by 1 or more halo), CHF₂, CH₂F,                CF₃, halo, C₁₋₆ alkyl (linear, branched, optionally                substituted by 1 or more halo, C₁₋₆ alkoxyl) or, if                applicable, taken together with an R¹ on an adjacent                bonded atom, together with the atoms they are attached                to, form a 3-6 membered ring alicyclic, aryl, or                heteroaryl system containing 0-2 heteroatoms, and R², R³                is independently H, halo, C₁₋₆ alkyl (optionally                substituted by 1 or more F) or taken together with the                atom they are attached to, form a 3-8 membered ring                system containing 0-2 heteroatoms.

    -   1.4 Compound 1.3, wherein A is:

-   -    wherein X is CH or N.    -   1.5 Compound 1.4 or 1.5, wherein B is:

-   -   1.6 Compound 1.1 or 1.2, wherein the compound has an AR binding        moiety as provided in a structure selected from the group        consisting of:

-   -   -   wherein:            -   Ring1 is 3-7 membered alicyclic with 0-4 heteroatoms and                substituted by 1 or more halo, CN, C≡CH, C₁₋₆ alkyl                (linear, branched, optionally substituted by 1 or more                halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy (linear, branched,                optionally substituted by 1 or more halo), C₂₋₆ alkenyl,                or C₂₋₆ alkynyl, bridged or spiro, bicyclic rings with                0-4 heteroatoms and substituted by 1 or more halo, CN,                C≡CH, C₁₋₆ alkyl (linear, branched, optionally                substituted by 1 or more halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy                (linear, branched, optionally substituted by 1 or more                halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl, or

-   -   -   -   Ring2 is aryl, 2-benzyloxy-3,4difluoro, heteroaryl                independently substituted by 1 or more halo, hydroxyl,                CN, C≡CH, NR¹⁰²R¹⁰³, OCH3, OC₁₋₃ alkyl (optionally                substituted by 1 or more halo), C₁₋₆ alkyl (linear                branched, optionally substituted by 1 or more halo, C₁₋₆                alkoxyl), C₁₋₆ alkoxyl (linear, branched, optionally                substituted by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆                alkynyl, 3-6 membered alicyclic with 0-4 heteroatoms and                substituted with 1 or more halo, hydroxyl, CN, C≡CH,                C₁₋₆ alkyl (linear, branched, optionally substituted by                1 or more halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy (linear,                branched, optionally substituted by 1 or more halo, C₁₋₆                alkoxy), C₁₋₆ alkoxyl (linear, branched, optionally                substituted by 1 or more halo), C₂₋₆ alkenyl, or C₂₋₆                alkynyl, wherein R¹⁰² and R¹⁰³ are independently H,                halo, C₁₋₆ alkyl (optionally substituted by 1 or more F)                or, taken together with the atom they are attached to,                form a 3-8 membered ring system containing 0-2                heteroatoms,

-   -   -   -   R¹⁰¹ is independently H, OH, CONH₂, CONR¹⁰²R¹⁰³, SONH₂,                SONR¹⁰²R¹⁰³, SO₂NH₂, SO₂NR¹⁰²R¹⁰³, NHCO—C₁₋₃ alkyl                (optionally substituted by 1 or more halo), NR¹⁰²COC₁₋₃                alkyl (optionally substituted by 1 or more halo),                NR²SO₂C₁₋₃ alkyl (optionally substituted by 1 or more                halo), NR¹⁰²SOC₁₋₃ alkyl (optionally substituted by 1 or                more halo), CN, C≡CH, NH₂, NR¹⁰²R¹⁰³, OCH₃, OC₁₋₃ alkyl                (optionally substituted by 1 or more halo), CHF₂, CH₂F,                CF₃, halo, C₁₋₆ alkyl (linear, branched, optionally                substituted by 1 or more halo, C₁₋₆ alkoxyl) or, taken                together with an R¹⁰¹ on an adjacent bonded atom,                together with the atoms they are attached to, form a 3-6                membered ring alicyclic, aryl, or heteroaryl system                containing 0-2 heteroatoms, wherein R¹⁰² and R¹⁰³ are                independently H, halo, C₁₋₆ alkyl (optionally                substituted by 1 or more F) or, taken together with the                atom they are attached to, form a 3-8 membered ring                system containing 0-2 heteroatoms.

    -   1.7 Any preceding compound, wherein the linker (“L” or “Link”)        comprises a chemical structure represented by -A_(q)-, in which        q is an integer greater than 1, and A is independently selected        from the group consisting of a bond, CR^(L1)R^(L2), O, S, SO,        SO₂, NR^(L3), SO₂NR^(L3), SONR^(L3), CONR^(L3),        NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO, CR^(L1)═CR^(L2), C≡C,        SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1), NR^(L3)C(═NCN)NR^(L4),        NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4), C₃₋₁₁ cycloaklyl        (optionally substituted with 0-6 R^(L1) and/or R^(L2) groups),        and heteroaryl (optionally substituted with 0-6 R^(L1) and/or        R^(L2) groups), wherein R^(L1), R^(L2), R^(L3), R^(L4) and        R^(L5) are each independently selected from the group consisting        of H, halo, C₁₋₈ alkyl, OC₁₋₈ alkyl, SC₁₋₈ alkyl, NHC₁₋₈ alkyl,        N(C₁₋₈ alkyl)₂, C₃₋₁₁ cycloalkyl, aryl, heteroaryl, C₃₋₁₁        heterocyclyl, OC₁₋₈ cycloalkyl, SC₁₋₈ cycloalkyl, NHC₁₋₈        cycloalkyl, N(C₁₋₈cycloalkyl)₂, N(C₁₋₈ cycloalkyl)(C₁₋₈ alkyl),        OH, NH₂, SH, SO₂C₁₋₈ alkyl, P(O)(OC₁₋₈ alkyl)(C₁₋₈ alkyl),        P(O)(OC₁₋₈ alkyl)₂, CC—C₁₋₈ alkyl, CCH, CH═CH(C₁₋₈ alkyl),        C(C₁₋₈ alkyl)═CH(C₁₋₈ alkyl), C(C₁₋₈ alkyl)═C(C₁₋₈ alkyl)₂,        Si(OH)₃, SiC(₁₋₈ alkyl)₃, Si(OH)(C₁₋₈ alkyl)₂, COC₁₋₈ alkyl,        CO₂H, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅, SO₂NHC₁₋₈ alkyl, SO₂NHC₁₋₈        alkyl, SO₂N(C₁₋₈ alkyl)₂, SONHC₁₋₈ alkyl, SON(C₁₋₈ alkyl)₂,        CONHC₁₋₈ alkyl, CON(C₁₋₈ alkyl)₂, N(C₁₋₈ alkyl)CONH(C₁₋₈ alkyl),        N(C₁₋₈ alkyl)CON(C₁₋₈ alkyl)₂, NHCONH(C₁₋₈ alkyl), NHCON(C₁₋₈        alkyl)₂, NHCONH₂, N(C₁₋₈ alkyl)SO₂NH(C₁₋₈ alkyl), N(C₁₋₈        alkyl)SO₂N(C₁₋₈ alkyl)₂, NHSO₂NH(C₁₋₈ alkyl), NHSO₂N(C₁₋₈        alkyl)₂ and NHSO₂NH₂, and wherein R^(L1) and R^(L2) each,        independently may be linked to another A group to form a        cycloalkyl and or heterocyclyl moiety that can be further        substituted with 0-4 R^(L5) groups.

    -   1.8 Any preceding compound, wherein the linker (e.g., “Link”)        comprises a structure selected from the group consisting of:

-   -   1.9 Any preceding compound, wherein the E3 ligase binding moiety        comprises a structure selected from the group consisting of:

wherein “

” in the above structures, represents a bond that may be stereospecific((R) or (S)), or non-stereospecific, and wherein:

R¹ is each independently H, OH, CONH₂, CONR²R³, SONH₂, SONR²R³, SO₂NH₂,SO₂NR²R³, NHCO—C₁₋₃ alkyl (optionally substituted by 1 or more halo),NR²COC₁₋₃ alkyl (optionally substituted by 1 or more halo), NR²SO₂C₁₋₃alkyl (optionally substituted by 1 or more halo), NR²SOC₁₋₃ alkyl(optionally substituted by 1 or more halo), CN, C═CH, NH₂, NR²R³, OCH₃,OC₁₋₃ alkyl (optionally substituted by 1 or more halo), CHF₂, CH₂F, CF₃,halo, C₁₋₆ alkyl (linear, branched, optionally substituted by 1 or morehalo, C₁₋₆ alkoxyl) or, if applicable, taken together with an R¹ on anadjacent bonded atom, together with the atoms they are attached to, forma 3-6 membered ring alicyclic, aryl, or heteroaryl system containing 0-2heteroatoms, and

R², R³ are each independently H, halo, C₁₋₆ alkyl (optionallysubstituted by 1 or more F) or taken together with the atom they areattached to, form a 3-8 membered ring system containing 0-2 heteroatoms;and

R⁴ is selected from H, alkyl (linear, branched, optionally substitutedwith R⁵), OH, R⁵OCOOR⁶, R⁵OCONR⁵R⁷, CH₂-heterocyclyl optionallysubstituted with R⁵, or benzyl optionally substituted with R⁵;

R⁵ and R⁷ are each independently a bond, H, alkyl (linear, branched),cycloalkyl, aryl, hetaryl heterocyclyl, or —C(═O)R⁶ each of which isoptionally substitute; and

R⁶ is selected from CONR⁵R⁷, OR⁵, NR⁵R⁷, SR⁵, SO₂R⁵, SO₂NR⁵R⁷, CR⁵R⁷,CR⁵NR⁵R⁷, aryl, hetaryl, alkyl (linear, branched, optionallysubstituted), cycloalkyl, heterocyclyl, P(O)(OR⁵)R⁷, P(O)R⁵R⁷,OP(O)(OR⁵)R⁷, OP(O)R⁵R⁷, Cl, F, Br, I, CF₃, CHF₂, CH₂F, CN, NR⁵SO₂NR⁵R⁷,NR⁵CONR⁵R⁷, CONR⁵COR⁷, NR⁵C(═N—CN)NR⁵R⁷, C(═N—CN)NR⁵R⁷, NR⁵C(—N═CN)R⁷,NR⁵C(═C—NO₂)NR⁵R⁷, SO₂NR⁵COR⁷, NO₂, CO₂R⁵, C(C═N—OR⁵)R⁷, CR⁵, CR⁵R⁷,CCR⁵, S(C═O)(C═N—R⁵)R⁷, SF₅, R⁵NR⁵R⁷, (R⁵O)_(n)R⁷, or OCF₃, where n isan integer from 1 to 10.

-   -   1.10 Any preceding compound, wherein the E3 ligase binding        moiety comprises a structure selected from:

-   -   -   wherein in each moiety:            -   R⁸ is H, a straight chain or branched C₁₋₈ alkyl (e.g.,                methyl, ethyl, isopropyl, tert-butyl), C₃₋₆ cycloalkyl                (e.g., cyclopropyl), halo, CFH₂, CF₂H, or CF₃;            -   R⁹ is a H, halo, 4-methylthiazol-5-ylm, or oxazol-5-yl;            -   R¹⁰ are independently optionally substituted alkyl                (e.g., methyl, ethyl, isopropyl, tert-butyl), optionally                substituted cycloalkyl (e.g., cyclopropyl), optionally                substituted cycloalkylalkyl, optionally substituted                arylalkyl, optionally substituted aryl, optionally                substituted thioalkyl wherein the substituents attached                to the S atom of the thioalkyl are optionally                substituted alkyl, optionally substituted branched                alkyl, optionally substituted heterocyclyl,                (CH₂)_(v)COR¹⁴, CH₂CHR¹⁵COR¹⁶ or CH₂R¹⁷, where v=1 to 3;            -   R¹⁴ and R¹⁶ are independently selected from OH, NR¹⁸R¹⁹,                or —OR²⁰ (as defined hereinbelow);            -   R¹⁵ is —NR¹⁸R¹⁹;            -   R¹⁷ is optionally substituted aryl or optionally                substituted heterocyclyl, where the optional                substituents include alkyl and halogen;            -   R¹⁸ is hydrogen or optionally substituted alkyl;            -   R¹⁹ is hydrogen, optionally substituted alkyl,                optionally substituted branched alkyl, optionally                substituted arylalkyl, optionally substituted                heterocyclyl, —CH₂(OCH₂CH₂O)_(v)CH₃, or a polyamine                chain, where w=1 to 8;            -   each R¹¹ is independently optionally substituted alkyl                (e.g., methyl, ethyl, isopropyl, tert-butyl), optionally                substituted cycloalkyl (e.g., cyclopropyl), optionally                substituted aryl, optionally substituted arylalkyl,                optionally substituted arylalkoxy, optionally                substituted heteroaryl, optionally substituted                heterocyclyl, optionally substituted heterocycloalkyl                wherein the substituents are alkyl, halogen, or OH.

    -   1.11 Any preceding compound, wherein the E3 ligase binding        moiety comprises a structure selected from the group consisting        of:

-   -   -   wherein:            -   R¹⁰ and R¹¹ are each as defined in Compound 1.9;            -   R¹² and R¹³ are independently hydrogen, optionally                substituted alkyl (e.g., methyl), or optionally                substituted cycloalkyl;            -   X is CH₂, NR², or O;            -   Y is S or O;            -   D is a bond (direct bond between X and L) or a ring                which may be aryl or heteroaryl, independently                substituted by 1 or more halo, hydroxyl, nitro, CN,                C≡CH, NR²R³, OCH₃, OC₁₋₃ alkyl (optionally substituted                by 1 or more halo), CF₃, C₁₋₆ alkyl (linear, branched,                optionally substituted by 1 or more halo, C₁₋₆ alkoxyl),                C₁₋₆ alkoxyl (linear, branched, optionally substituted                by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-6                membered alicyclic with 0-4 heteroatoms and substituted                by 1 or more halo, hydroxyl, nitro, CN, C≡CH, CF₃, C₁₋₆                alkyl (linear, branched, optionally substituted by 1 or                more halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy (linear, branched,                optionally substituted by 1 or more halo), C₂₋₆ alkenyl,                or C₂₋₆ alkynyl;            -   R², R³ are each independently H, halo, C₁₋₆ alkyl                (optionally substituted by 1 or more F) or taken                together with the atom they are attached to, form a 3-8                membered ring system containing 0-2 heteroatoms; and            -   R²⁰ is selected from the group consisting of.

-   -   -   -   wherein A is a C₄₋₈ aliphatic ring, and B is an aryl                (e.g., phenyl) or N-containing heteroaryl (e.g.,                pyridyl) and each is optionally substituted by alkyl or                haloalkyl.

    -   1.12 Any preceding compound, wherein the E3 ligase binding        moiety is:

-   -   -   wherein:            -   R²² is aryl (e.g. phenyl) or heteroaryl (e.g., pyridyl)                optionally substituted by halogen (e.g., F or Cl), e.g.,                mono-, di or tri-substituted independently by halogen;            -   R²¹ is aryl (e.g. phenyl) or heteroaryl (e.g., pyridyl),                optionally substituted by halogen (e.g., F or Cl), e.g.,                mono-, di- or tri-substituted by halogen, CN, ethynyl,                cyclopropyl, methyl, ethyl, isopropyl, methoxy, ethoxy,                isopropoxy, other C₁₋₆ alkyl, other C₁₋₆ alkenyl and                C₁₋₆ alkynyl;            -   R²³ is selected from alkyl (e.g., methyl, ethyl,                isopropyl, propyl, n-butyl, sec-butyl, isobutyl,                t-butyl, n-pentyl, t-pentyl, isoamyl, neopentyl,                n-hexyl), substituted alkyl, alkenyl, substituted                alkenyl, substituted alkynyl, aryl, substituted aryl,                heteroaryl, substituted heteroaryl, cycloalkyl,                substituted cycloalkyl, alkenyl and substituted                cycloalkenyl;            -   R²⁴ is H, alkyl (e.g., methyl), aryl, substituted alkyl,                cycloalkyl, aryl substituted cycloalkyl and alkoxy                substituted cycloalkyl; and E is para-substituted                (1,4-disubstituted) aryl (e.g., phenyl), single or                multiple N containing heteroaryl (e.g., pyridyl,                pyrimidinyl, pyrazinyl, pyridazinyl), each optionally                further substituted by —OCH₃, —OCH₂CH₃ and halogen.

    -   1.13 Any preceding compound, wherein the E3 ligase binding        moiety is a cereblon binding fragment, e.g., selected from        thalidomide, pomalidomide, and lenalidomide

    -   1.14 Any preceding compound, wherein the E3 ligase binding        moiety is an E3 CRL2^(VHL) moiety, or an IAP or MDM2-binding        moiety.

    -   1.15 Any preceding compound, wherein the compound has an E3        ligase binding moiety as provided in a structure selected from        the group consisting of:

-   -   -   wherein:            -   R¹⁰⁴ is independently H, OH, CONH₂, CONR¹⁰²R¹⁰³, SONH₂,                SONR¹⁰²R¹⁰³, SO₂NH₂, SO₂NR¹⁰²R¹⁰³, NHCO C₁₋₃ alkyl                (optionally substituted by one or more halo),                NR¹⁰²COC₁₋₃ alkyl (optionally substituted by one or more                halo), NR²SO₂C₁₋₃ alkyl (optionally substituted by one                or more halo), NR¹⁰²SOC₁₋₃ alkyl (optionally substituted                by one or more halo), CN, C═CH, NH₂, NR¹⁰²R¹⁰³, OCH₃,                OC₁₋₃ alkyl (optionally substituted by one or more                halo), CHF₂, CH₂F, CF₃, halo, C₁₋₆ alkyl (linear,                branched, optionally substituted by one or more halo,                C₁₋₆ alkoxyl) or, taken together with an R¹⁰¹ on an                adjacent bonded atom, together with the atoms they are                attached to, form a 3-6 membered ring alicyclic, aryl,                or heteroaryl system containing 0-2 heteroatoms, wherein                and R¹⁰², R¹⁰³ is independently H, halo, C₁₋₆ alkyl                (optionally substituted by one or more F) or taken                together with the atom they are attached to, form a 3-8                membered ring system containing 0-2 heteroatoms,            -   R¹⁰⁵ is independently H, C₁₋₆ alkyl (optionally                substituted by one or more F), and            -   X is NH or O.

    -   1.16 Any preceding compound, wherein the compound has an E3        ligase binding moiety which is a Von-Hippel-Lindau Ligase        binding moiety as provided in a structure selected from the        group consisting of:

-   -   -   wherein            -   R¹⁰⁶ is isopropyl, tert-butyl, sec-butyl, cyclopentyl,                cyclohexyl, cyclopropyl or haloalkyl,            -   R¹⁰⁷ is H, haloalkyl, methyl, ethyl, isopropyl,                cyclopropyl or C₁-C₆ alkyl (linear, branched, optionally                substituted), each optionally substituted with one or                more halo, hydroxyl, CN, C₁-C₆ alkyl (linear, branched,                optionally substituted), or C₁-C₆ alkoxyl (linear,                branched, optionally substituted),            -   R¹⁰⁸ is H or a prodrug group,            -   R¹⁰⁹ is H, halo, optionally substituted C₃₋₆ cycloalkyl,                optionally substituted C₁₋₆ alkyl. Optionally                substituted C₁₋₆ alkenyl or C₁₋₆ haloalkyl, and            -   X is S or O.

    -   1.17 Any preceding compound, wherein the compound has an E3        ligase binding moiety as provided in a structure selected from        the group consisting of:

-   -   -   wherein:        -   R¹¹⁰ are independently hydrogen, optionally substituted            alkyl or optionally substituted cycloalkyl,        -   R¹¹¹ are independently hydrogen, optionally substituted            alkyl or optionally substituted cycloalkyl,        -   R¹¹² are independently optionally substituted alkyl,            optionally substituted cycloalkyl, optionally substituted            cycloalkylalkyl, optionally substituted arylalkyl,            optionally substituted aryl, optionally substituted            thioalkyl wherein the substituents attached to the S atom of            the thioalkyl are optionally substituted branched alkyl,            optionally substituted heterocyclyl, —(CH₂)COR¹¹⁵,            —CH₂CHR¹¹⁶COR¹¹⁷ or CH₂R¹¹⁸, where v=1-3, R¹¹⁵ and R¹¹⁷ are            independently selected from OH, NR¹¹⁸R¹¹⁹ or OR¹²⁰, R¹¹⁶ is            NR¹¹⁸R¹¹⁹, R¹¹⁸ is optionally substituted aryl or optionally            substituted heterocyclyl where the optional substituents            include alkyl and halogen, and R¹¹⁹ is hydrogen or            optionally substituted alkyl,        -   R¹¹³ is selected from the group consisting of

-   -   -    where B is an aryl or N-containing heteroaryl and            optionally substituted by alkyl or haloalkyl,        -   R¹¹⁴ is selected from the group consisting of

wherein A is a C₄₋₈ aliphatic ring, B is an aryl or N-containingheteroaryl and optionally substituted by alkyl or haloalkyl. Y is N, O,C═O, or S, and

-   -   X is S or O.    -   1.18 Any preceding compound, wherein the compound has an E3        ligase binding moiety which is an MDM2 homolog inhibitor as        provided in a structure selected from the group consisting of:

-   -   -   wherein:            -   Ring3 is para-substituted aryl, single or multiple N                containing heteroaryl optionally substituted by —OCH3,                —OCH2CH₃, or halogen,            -   R¹²¹ is independently aryl or heteroaryl, optionally                substituted by mono-, di- or tri-substituted halogen,                —CN, ethynyl, cyclopropyl, methyl, ethyl, isopropyl,                methoxy, ethoxy, isopropoxy, other C₁₋₆ alkyl, other                C₁₋₆ alkenyl and C₁₋₆ alkynyl,            -   R¹²² is independently aryl or heteroaryl optionally                substituted by halogen, or mono, di, or tri-substituted                halogen,            -   R¹²³ is selected from alkyl, substituted alkyl, alkenyl,                substituted alkenyl, substituted alkynyl, aryl,                substituted aryl, heteroaryl, substituted heteroaryl,                cycloalkyl, substituted cycloalkyl, alkenyl and                substituted cycloalkenyl, and            -   R¹²⁴ is selected from H, alkyl, aryl, substituted alkyl,                cycloalkyl, aryl substituted cycloalkyl and alkoxy                substituted cycloalkyl.

    -   1.19 Any preceding compound, wherein the AR binding moiety is        selected from:

-   -    wherein:        -   A is a 3-7 membered alicyclic ring with 0-4 heteroatoms            (e.g., morpholinyl), B is aryl (e.g., phenyl) or heteroaryl            (e.g., imidazolyl) optionally substituted by one or more            halo, and R¹ is H, OH, CN, NH₂, OCH₃, halo, or C₁₋₆ alkyl;            or

-   -   -    wherein:        -   A is a 3-7 membered alicyclic ring with 0-4 heteroatoms            (e.g., morpholinyl), and R¹ is H, OH, CN, NH₂, OCH₃, halo,            or C₁₋₆ alkyl.

    -   1.20 Compound 1.19, wherein A is selected from morpholinyl,        piperazinyl, N-methylpiperazinyl, piperidinyl, and pyrrolidinyl.

    -   1.21 Compound 1.20, wherein A is morpholinyl (e.g.,        1-morpholinyl).

    -   1.22 Any of Compounds 1.19 to 1.21, wherein R¹ is H or halo.

    -   1.23 Any of Compounds 1.19 to 1.22, wherein B is phenyl        optionally substituted by one or two halo (e.g., fluoro, chloro        or bromo) or B is imidazolyl optionally substituted by one or        two halo (e.g., fluoro, chloro or bromo).

    -   1.24 Compound 1.23, wherein B is:

-   -    wherein each R¹ is independently H or F.    -   1.25 Any preceding compound, wherein the AR binding moiety is        selected from:

-   -   1.26 Any preceding compound, wherein the AR binding moiety is:

-   -   1.27 Any preceding compound, wherein the E3 ligase binding        moiety is selected from:

-   -    each as described hereinabove.    -   1.28 Compound 1.27, wherein each R¹ (of the E3LB) is        independently selected from H, OH, CN, NH₂, OCH₃, halo, or C₁₋₆        alkyl; R⁴ is H or C₁₋₃ alkyl (e.g., methyl); R⁸ is H, halo, or        C₁₋₆ alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl); R¹⁰ is        H, halo, or optionally substituted C₁₋₆ alkyl (e.g., methyl,        ethyl, isopropyl, tert-butyl) or C₃₋₆ cycloalkyl (e.g.,        cyclopropyl); R¹¹ is H, optionally substituted C₁₋₆ alkyl (e.g.,        methyl, ethyl, isopropyl, tert-butyl), or optionally substituted        C₃₋₁₀ cycloalkyl (e.g., cyclopropyl); R¹² and R¹³ are each        independently H or C₁₋₆ alkyl (e.g., methyl); R²⁰ is CH(aryl)₂        (e.g. CHPh₂); R²¹ and R²² are each aryl (e.g., phenyl)        optionally substituted by halogen (e.g., F or Cl); R²³        optionally substituted C₁₋₁₀ alkyl (e.g., methyl, ethyl,        isopropyl, propyl, n-butyl, sec-butyl, isobutyl, t-butyl,        n-pentyl, t-pentyl, isoamyl, neopentyl, n-hexyl); R²⁴ is H or        C₁₋₆ alkyl; and E is para-substituted phenyl optionally        substituted by OCH₃.    -   1.29 Compound 1.27, wherein R¹ is H; R⁴ is H; R⁸ is C₁₋₆ alkyl        (e.g., tert-butyl); R¹⁰ is optionally substituted C₁₋₆ alkyl        (e.g., methyl or tert-butyl) or C₃₋₆ cycloalkyl (e.g.,        cyclohexyl); R¹¹ is optionally substituted C₃₋₁₀ cycloalkyl        (e.g., cyclopropyl or tetrahydronapthyl); R¹² and R¹³ are each        independently C₁₋₆ alkyl (e.g. methyl); R²⁰ is CH(phenyl)₂; R²¹        and R²² are each phenyl optionally substituted by one or two        halogen (e.g., F or Cl); R²³ C₁₋₆ alkyl (e.g., tert-amyl); R²⁴        is H; and E is para-substituted phenyl optionally substituted by        OCH₃.    -   1.30 Compound 1.27, wherein R¹ is H; R⁴ is H; R¹⁰ is tert-butyl;        R¹⁰ is methyl, tert-butyl or cyclohexyl; R¹¹ is cyclopropyl or        tetrahydronapthyl each optionally substituted with halo (e.g.,        fluoro); R¹² and R¹³ are each independently methyl; R²⁰ is        CH(phenyl)₂; R²¹ and R²² are each phenyl optionally substituted        by one or two halogen (e.g., F or Cl); R²³ tert-amyl; R²⁴ is H;        and E is para-substituted phenyl substituted by one OCH₃.    -   1.31 Any preceding compound, wherein the E3 ligase binding        moiety is selected from the group consisting of:

-   -   1.32 Any preceding compound, wherein the linker group (e.g.,        “L”) is selected from:

-   -    wherein n is from 1-5;

-   -    wherein n is from 1-5;

-   -    wherein n is from 1-5;

-   -    wherein m is from 0-12;

-   -    wherein m is from 0-12;

-   -    wherein m is from 0-12;

-   -    wherein m is from 2-4;

-   -    wherein m is from 0-12;

-   -    wherein m is from 0-10;

-   -    wherein n is from 1-5;

-   -    wherein n is from 1-5;

-   -    wherein n is from 1-5;

-   -    wherein m is from 0-10;

-   -    wherein m is from 0-10;

-   -    wherein m is from 0-10;

-   -    wherein n is from 1-5;

-   -    wherein n is from 1-5;

-   -    wherein n is from 1-5;

-   -    wherein n is from 1-5;

-   -    wherein n is from 1-5;

-   -    wherein m is from 1-12;

-   -    wherein m is from 1-12;

-   -    wherein m is from 1-12; and

-   -    wherein m is from 0-10.    -   1.33 Any preceding compound, wherein the linker group is        selected from:

-   -    wherein n is from 2-4;

-   -    wherein n is from 2-4;

-   -    wherein n is from 2-3;

-   -    wherein m is from 2-8;

-   -    wherein m is from 4-8;    -    wherein m is from 2-4;

-   -    wherein m is from 2-4;

-   -    wherein m is from 1-4;

-   -    wherein m is from 1-4;

-   -    wherein n is from 2-4;

-   -    wherein n is from 1-3;

-   -    wherein n is from 1-2;

-   -    wherein m is from 4-6;

-   -    wherein m is from 2-4; and

-   -    wherein m is from 2-4.    -   1.34 Any preceding compound, wherein the compound comprises an        AR binding moiety as defined in section 1.25, and an E3 ligase        binding moiety as defined in section 1.31, and a linker as        defined in section 1.32.    -   1.35 Any preceding compound, wherein the compound comprises an        AR binding moiety as defined in section 1.26, and an E3 ligase        binding moiety as defined in section 1.31, and a linker as        defined in section 1.32.    -   1.36 Any preceding compound, wherein the compound comprises an        AR binding moiety as defined in section 1.25, and an E3 ligase        binding moiety as defined in section 1.31, and a linker as        defined in section 1.33.    -   1.37 Any preceding compound, wherein the compound comprises an        AR binding moiety as defined in section 1.26, and an E3 ligase        binding moiety as defined in section 1.31, and a linker as        defined in section 1.33.    -   1.38 Any preceding compound, wherein the compound comprises:        -   the AR binding moiety

-   -   -   the E3 ligase binding moiety

-   -   -    and        -   a linker selected from:

-   -   -    wherein n is from 1-5;

-   -   -    wherein n is from 1-5;

-   -   -    wherein m is from 0-12;

-   -   -    wherein m is from 2-4;

-   -   -    wherein m is from 0-12; and

-   -   -    wherein m is from 0-10.

    -   1.39 Any preceding compound, wherein the compound comprises:        -   the AR binding moiety

-   -   -   the E3 ligase binding moiety

-   -   -    and        -   a linker selected from:

-   -   -    wherein n is from 1-5;

-   -   -    wherein m is from 0-12;

-   -   -    wherein n is from 1-5; and

-   -   -    wherein m is from 1-12.

    -   1.40 Any preceding compound, wherein the compound is selected        from any one or more of Examples 1 to 35 in the table above.

    -   1.41 Any preceding compound, wherein the compound is selected        from the group consisting of:

-   (a)    2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide,

-   (b)    2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)acetamide,

-   (c)    (2S,4R)-1-((S)-2-(4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide,

-   (d)    (2S,4R)-1-((S)-2-(5-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide,

-   (e)    (2S,4R)-1-((S)-2-(6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide,

-   (f)    (2S,4R)-1-((S)-2-(7-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide,

-   (g)    (2S,4R)-1-((S)-2-(2-(3-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide,

-   (h)    (2S,4R)-1-((S)-2-(tert-butyl)-14-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-4,13-dioxo-6,9-dioxa-3,12-diazatetradecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide,

-   (i)    (2S,4R)-1-((S)-2-(8-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide,

-   (j)    (S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide,

-   (k)    (S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide,

-   (l)    (S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide,

-   (m) (2R,3    S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide,

-   (n)    (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide,

-   (o)    (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide,

-   (p)    N-(5-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)-2-morpholinobenzo[d]thiazole-4-carboxamide,    and

-   (q)    N-(6-((S)-2-((S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanamido)hexyl)-2-morpholinobenzo[d]thiazole-4-carboxamide.    -   1.42 Any preceding compound, wherein the compound is selected        from:

-   (a)    (2S,4R)-1-((S)-2-(5-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

-   (b)    (S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide;    and

-   (c)    (S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide.    -   1.43 Any of Compounds 1.1-1.42 wherein the compound is effective        in causing or promoting the degradation of the androgen receptor        (AR) in a cell, or of causing or promoting apoptosis in a cell.    -   1.44 Compound 1.43, wherein the cell is a cancer cell (e.g., a        prostate cancer cell or ovarian cancer cell, for example,        castration-resistant prostate cancer (CRPC) cell).    -   1.45 Compound 1.43 or 1.44, wherein the cell overexpresses the        AR or expresses a mutated AR, such as an AR having a truncated        ligand binding domain or absent ligand binding domain.    -   1.46 Compound 1.45, wherein the mutant AR is any AR-V1 to AR-V15        splice variant, e.g., the AR-V7 splice variant.    -   1.47 A pharmaceutical composition comprising any of Compounds        1.1-1.46 (e.g., an effective amount of any of Compounds        1.1-1.46), and a pharmaceutically acceptable carrier, additive        and/or excipient.    -   1.48 Pharmaceutical Composition 1.47, further comprising at        least one additional anticancer agent.    -   1.49 Any of Compounds 1.1-1.46, or pharmaceutical composition        1.47 or 1.48, for use in the treatment of a disease state or        condition in a patient wherein dysregulated protein activity is        responsible for said disease or condition.    -   1.50 Use of any of Compounds 1.1-1.46, or pharmaceutical        composition 1.47 or 1.48, in the treatment of a disease state or        condition in a patient wherein dysregulated protein activity is        responsible for said disease or condition.    -   1.51 A Method of treating a disease state or condition in a        patient wherein dysregulated protein activity is responsible for        said disease or condition, said method comprising administering        an effective amount of any of Compounds 1.1-1.46, or        pharmaceutical composition 1.47 or 1.48, to a patient in need        thereof.    -   1.52 Any of the Uses or Methods according to 1.49 to 1.51,        wherein the disease or condition is a cancer.    -   1.53 Any of the Uses or Methods according to 1.49 to 1.52,        wherein the disease or condition is a cancer identified as        having a mutation resulting, or expected to result in,        overexpression of the androgen receptor.    -   1.54 Use or Method 1.53, wherein the cell expresses a mutated        androgen receptor, e.g., one in which there is a mutation in the        ligand binding domain of the AR.    -   1.55 Use or Method 1.54, wherein the ligand binding domain of        the AR is truncated or absent.    -   1.56 Any of Uses or Methods 1.51-1.55, wherein the cell        expresses or overexpresses any AR-V1 to AR-V15 splice variant,        e.g., the AR-V7 splice variant.    -   1.57 Any of the uses or methods according to 1.52 to 1.56,        wherein the cancer is a prostate cancer or ovarian cancer.    -   1.58 Use or Method 1.57, wherein the cancer is a prostate        cancer, for example, castration-resistant prostate cancer        (CRPC).    -   1.59 Any of the uses or methods according to 1.49 to 1.58,        wherein the disease or condition is not responsive to, or no        longer responsive to, treatment with an androgen receptor        antagonist (e.g., abiraterone, apalutamide, enzalutamide, or        darolutamide).    -   1.60 Any of Compounds 1.1-1.46, or pharmaceutical composition        1.47 or 1.48, for use in the degradation of an androgen receptor        in a cell, e.g., a mutated AR such as any AR-V1 to AR-V15 splice        variant, e.g., the AR-V7 splice variant.    -   1.61 Use of any of Compounds 1.1-1.46, or pharmaceutical        composition 1.47 or 1.48, in the degradation of an androgen        receptor (AR) in a cell, e.g., a mutated AR such as any AR-V1 to        AR-V15 splice variant, e.g., the AR-V7 splice variant.    -   1.62 A Method of degrading an androgen receptor in a cell, e.g.,        a mutated AR such as any AR-V1 to AR-V15 splice variant, e.g.,        the AR-V7 splice variant, said method comprising administering        an effective amount of any of Compounds 1.1-1.46, or        pharmaceutical composition 1.47 or 1.48, to such cell.    -   1.63 Any of Uses or Methods 1.60-1.62, wherein the cell is a        cancer cell (e.g., a prostate cancer cell or ovarian cancer        cell, for example, castration-resistant prostate cancer (CRPC)        cell).    -   1.64 Any of Uses or Methods 1.60-1.63, wherein the cell        overexpresses the AR or expresses a mutated AR, such as an AR        having a truncated ligand binding domain or absent ligand        binding domain.    -   1.65 Use or Method 1.64, wherein the mutant AR is any AR-V1 to        AR-V15 splice variant, e.g., the AR-V7 splice variant.    -   1.66 Any of Uses or Methods 1.60-1.65, wherein the AR is        resistant to inhibition by an AR antagonist (e.g., abiraterone,        apalutamide, enzalutamide, or darolutamide).    -   1.67 Any of Compounds 1.1-1.46, or pharmaceutical composition        1.47 or 1.48, for use in inducing apoptosis in a cell, e.g., a        cancer cell.    -   1.68 Use of any of Compounds 1.1-1.46, or pharmaceutical        composition 1.47 or 1.48, in the induction of apoptosis in a        cell, e.g., a cancer cell.    -   1.69 A Method of inducing apoptosis in a cell, e.g., a cancer        cell, said method comprising administering an effective amount        of any of Compounds 1.1-1.46, or pharmaceutical composition 1.47        or 1.48, to such cell.    -   1.70 Any of Uses or Methods 1.67-1.69, wherein the cell is a        prostate cancer cell or ovarian cancer cell (for example,        castration-resistant prostate cancer (CRPC) cell).    -   1.71 Any of Uses or Methods 1.67-1.70, wherein the cell        overexpresses the androgen receptor (AR) or expresses a mutated        AR, such as an AR having a truncated ligand binding domain or        absent ligand binding domain.    -   1.72 Use or Method 1.71, wherein the mutant AR is any AR-V1 to        AR-V15 splice variant, e.g., the AR-V7 splice variant.    -   1.73 Any of Uses or Methods 1.60-1.72, wherein the cell is from        a patient suffering from or diagnosed with cancer.    -   1.74 Any of Uses or Methods 1.60-1.72, wherein the cell is in a        patient suffering from or diagnosed with cancer.

Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. The terminology used in thedescription is for describing particular embodiments only and is notintended to be limiting of the invention.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms in which case each carbon atomnumber falling within the range is provided), between the upper andlower limit of that range and any other stated or intervening value inthat stated range is encompassed within the invention. The upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the invention.

The following terms are used to describe the present disclosure. Ininstances where a term is not specifically defined herein, that term isgiven an art-recognized meaning by those of ordinary skill applying thatterm in context to its use in describing the present invention.

The articles “a” and “an” as used herein and in the claims are usedherein to refer to one or to more than one (i.e., to at least one) ofthe grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

The phrase “and/or” as used herein and in the claims should beunderstood to mean “either or both” of the elements so conjoined, i.e.,elements that are conjunctively present in some cases and disjunctivelypresent in other cases. Multiple elements listed with “and/or” should beconstrued in the same fashion, i.e., “one or more” of the elements soconjoined. Other elements may optionally be present other than theelements specifically identified by the “and/or” clause, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, a reference to “A and/or B”, when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A only (optionally including elements other than B);in another embodiment, to B only (optionally including elements otherthan A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, the term “or”should be understood to have the same meaning as “and/or” as definedabove. For example, when separating items in a list, “or” or “and/or”shall be interpreted as being inclusive, i.e., the inclusion of at leastone, but also including more than one, of a number or list of elements,and, optionally, additional unlisted items. Only terms clearly indicatedto the contrary, such as “only one of” or “exactly one of,” or, whenused in the claims, “consisting of,” will refer to the inclusion ofexactly one element of a number or list of elements. In general, theterm “or” as used herein shall only be interpreted as indicatingexclusive alternatives (i.e., “one or the other but not both”) whenpreceded by terms of exclusivity, such as “either,” “one of,” “only oneof,” or “exactly one of.”

The term “about” and the like, as used herein, in association withnumeric values or ranges, reflects the fact that there is a certainlevel of variation that is recognized and tolerated in the art due topractical and/or theoretical limitations. For example, minor variationis tolerated due to inherent variances in the manner in which certaindevices operate and/or measurements are taken. In accordance with theabove, the term “about” is normally used to encompass values within thestandard deviation or standard error.

In the claims, as well as in the specification, all transitional phrasessuch as “comprising,” “including,” “carrying,” “having,” “containing,”“involving,” “holding,” “composed of,” and the like are to be understoodto be open-ended, i.e., to mean “including without limitation”. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, Section 2111.03.

It should also be understood, that although various compounds,compositions, and methods are described in “open” terms of “comprising,”“including,” or “having” various components or steps (interpreted asmeaning “including without limitation”), the compounds, compositions,methods, and devices can also “consist essentially of” or “consist of”the various components and steps, and such terminology should beinterpreted as defining essentially closed-member groups. This paragraphis not meant in any way to limit the meaning of “comprising,” “having,”or “including” (and other verb forms thereof) which are to beinterpreted as open-ended phrases meaning “including without limitation”consistent with patent law and custom. The intent of this paragraph ismerely to indicate that the closed-member groups defined by the“consisting of” or “consisting essentially of” language are lesserincluded groups within the open-ended descriptions and to providesupport for claims employing the “consisting of” or “consistingessentially of” language.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from anyone or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, in certain methods described hereinthat include more than one step or act, the order of the steps or actsof the method is not necessarily limited to the order in which the stepsor acts of the method are recited unless the context indicatesotherwise.

The terms “co-administration” and “co-administering” or “combinationtherapy” can refer to both concurrent administration (administration oftwo or more therapeutic agents at the same time) and time variedadministration (administration of one or more therapeutic agents at atime different from that of the administration of an additionaltherapeutic agent or agents), as long as the therapeutic agents arepresent in the patient to some extent, preferably at effective amounts,at the same time. In certain preferred aspects, one or more of thepresent compounds described herein, are co-administered in combinationwith at least one additional bioactive agent, especially including ananticancer agent. In particularly preferred aspects, theco-administration of compounds results in synergistic activity and/ortherapy, including anticancer activity.

The term “effective” can mean, but is in no way limited to, thatamount/dose of the active pharmaceutical ingredient, which, when used inthe context of its intended use, effectuates or is sufficient toprevent, inhibit the occurrence, ameliorate, delay or treat (alleviate asymptom to some extent, preferably all) the symptoms of a condition,disorder or disease state in a subject in need of such treatment orreceiving such treatment. The term effective subsumes all othereffective amount or effective concentration terms, e.g., “effectiveamount/dose,” “pharmaceutically effective amount/dose” or“therapeutically effective amount/dose,” which are otherwise describedor used in the present application.

The effective amount depends on the type and severity of disease, thecomposition used, the route of administration, the type of mammal beingtreated, the physical characteristics of the specific mammal underconsideration, concurrent medication, and other factors which thoseskilled in the medical arts will recognize. The exact amount can beascertainable by one skilled in the art using known techniques (see,e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd,The Art, Science and Technology of Pharmaceutical Compounding (1999);Pickar, Dosage Calculations (1999); and Remington, The Science andPractice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott,Williams & Wilkins).

The term “pharmacological composition,” “therapeutic composition,”“therapeutic formulation” or “pharmaceutically acceptable formulation”can mean, but is in no way limited to, a composition or formulation thatallows for the effective distribution of an agent provided by thepresent disclosure, which is in a form suitable for administration tothe physical location most suitable for their desired activity, e.g.,systemic administration.

The term “pharmaceutically acceptable” can mean, but is in no waylimited to, entities and compositions that do not produce an adverse,allergic or other untoward reaction when administered to a patient orsubject.

The term “pharmaceutically acceptable carrier” can mean, but is in noway limited to, any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration to apatient or subject. Suitable carriers are described in the most recentedition of Remington's Pharmaceutical Sciences, a standard referencetext in the field, which is incorporated herein by reference. Preferredexamples of such carriers or diluents include, but are not limited to,water, saline, ringer's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe compositions is contemplated. Supplementary active compounds canalso be incorporated into the compositions.

The term “systemic administration” refers to a route of administrationthat is, e.g., enteral or parenteral, and results in the systemicdistribution of an agent leading to systemic absorption or accumulationof drugs in the blood stream followed by distribution throughout theentire body. Suitable forms, in part, depend upon the use or the routeof entry, for example oral, transdermal, or by injection. Such formsshould not prevent the composition or formulation from reaching a targetcell (i.e., a cell to which the negatively charged polymer is desired tobe delivered to). For example, pharmacological compositions injectedinto the blood stream should be soluble. Other factors are known in theart, and include considerations such as toxicity and forms which preventthe composition or formulation from exerting its effect. Administrationroutes which lead to systemic absorption include, without limitations:intravenous, subcutaneous, intraperitoneal, inhalation, oral,intrapulmonary and intramuscular.

The rate of entry of a drug into the circulation has been shown to be afunction of molecular weight or size. The use of a liposome or otherdrug carrier comprising the compounds of the instant disclosure canpotentially localize the drug, for example, in certain tissue types,such as the tissues of the reticular endothelial system (RES). Aliposome formulation which can facilitate the association of drug withthe surface of cells, such as, lymphocytes and macrophages is alsouseful.

The terms “patient” and “subject” are used throughout the specificationto describe a cell, tissue, or animal, preferably a mammal, e.g., ahuman or a domesticated animal, to whom treatment, includingprophylactic treatment, with the compositions according to the presentdisclosure is provided. For treatment of those infections, conditions ordisease states which are specific for a specific animal such as a humanpatient, the term patient refers to that specific animal, including adomesticated animal such as a dog or cat or a farm animal such as ahorse, cow, sheep, etc. In general, in the present disclosure, the termpatient refers to a human patient unless otherwise stated or impliedfrom the context of the use of the term.

The term “compound,” as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, and where applicable,stereoisomers, including optical isomers (enantiomers) and otherstereoisomers (diastereomers) thereof, as well as pharmaceuticallyacceptable salts and derivatives thereof where applicable, in context.Within its use in context, the term compound generally refers to asingle compound, but also may include other compounds such asstereoisomers, regioisomers and/or optical isomers (including racemicmixtures) as well as specific enantiomers or enantiomerically enrichedmixtures of disclosed compounds. The term also refers, in context toprodrug forms of compounds which have been modified to facilitate theadministration and delivery of compounds to a site of activity. The termalso refers to any specific chemical compound in which one or more atomshave been replaced with one or more different isotopes of the sameelement. It is noted that in describing the present compounds, numeroussubstituents and variables associated with same, among others, aredescribed.

It is understood by those of ordinary skill that molecules which aredescribed herein are stable compounds as generally described hereunder.When the bond is shown, both a double bond and single bond arerepresented or understood within the context of the compound shown andwell-known rules for valence interactions.

As used herein, “derivatives” can mean compositions formed from thenative compounds either directly, by modification, or by partialsubstitution. As used herein, “analogs” can mean compositions that havea structure similar to, but not identical to, the native compound.

The term “ubiquitin ligase” refers to a family of proteins thatfacilitate the transfer of ubiquitin to a specific substrate protein,targeting the substrate protein for degradation. For example, cereblonis an E3 ubiquitin ligase protein that alone or in combination with anE2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to alysine on a target protein, and subsequently targets the specificprotein substrates for degradation by the proteasome. Thus, E3 ubiquitinligase alone or in complex with an E2 ubiquitin conjugating enzyme isresponsible for the transfer of ubiquitin to targeted proteins. Ingeneral, the ubiquitin ligase may be involved in polyubiquitination suchthat a second ubiquitin may be attached to the first; a third may beattached to the second, and so forth. Polyubiquitination marks proteinsfor degradation by the proteasome. However, there are someubiquitination events that are limited to mono-ubiquitination, in whichonly a single ubiquitin is added by the ubiquitin ligase to a substratemolecule. Mono-ubiquitinated proteins may not be targeted to theproteasome for degradation, but may instead be altered in their cellularlocation or function, for example, via binding other proteins that havedomains capable of binding ubiquitin. Further, different lysines onubiquitin can be targeted by an E3 to make chains. The most commonlysine is Lys48 on the ubiquitin chain. This is the lysine used to makepolyubiquitin, which is recognized by the proteasome.

As used herein, the terms “halo” or “halogen” means fluoro (F), chloro(Cl), bromo (Br) or iodo (I).

As used herein, the term “hydrocarbyl” means a compound which containscarbon and hydrogen and which may be fully saturated, partiallyunsaturated or aromatic and includes aryl groups, alkyl groups, alkenylgroups and alkynyl groups.

As used herein, the term “alkyl” means within its context a linear,branch-chained, or cyclic fully saturated hydrocarbon radical or alkylgroup, preferably a C₁-C₁₀, more preferably a C₁-C₆, alternatively aC₁-C₃ alkyl group, which may be optionally substituted. Examples ofalkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl,cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl,cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and cyclohexyl,among others.

As used herein, the term “alkenyl” refers to linear, branched orbranch-chained, or cyclic C₂-C₁₀ (preferably C₂-C₆) hydrocarbon radicalscontaining at least one C═C bond.

As used herein, the term “Alkynyl” refers to linear, branched orbranch-chained, or cyclic C₂-C₁₀ (preferably C₂-C₆) hydrocarbon radicalscontaining at least one C≡C bond.

As used herein, the term “alkylene” refers to a —(CH₂)_(n)— group(wherein n is an integer generally from 0-6), which may be optionallysubstituted. When substituted, the alkylene group preferably issubstituted on one or more of the methylene groups with a C₁-C₆ alkylgroup (including a cyclopropyl group or a t-butyl group), morepreferably a methyl group, but may also be substituted with one or morehalo groups, preferably from 1 to 3 halo groups or one or two hydroxylgroups, O—(C₁-C₆ alkyl) groups or amino acid sidechains as otherwisedisclosed herein. In certain embodiments, an alkylene group may besubstituted with a urethane or alkoxy group (or other group) which isfurther substituted with a polyethylene glycol chain (of from 1 to 10,preferably 1 to 6, often 1 to 4 ethylene glycol units) to which issubstituted (preferably, but not exclusively on the distal end of thepolyethylene glycol chain) an alkyl chain substituted with a singlehalogen group, preferably a chlorine group. In still other embodiments,the alkylene (often, a methylene) group, may be substituted with anamino acid sidechain group such as a sidechain group of a natural orunnatural amino acid, for example, alanine, (3-alanine, arginine,asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine,glycine, phenylalanine, histidine, isoleucine, lysine, leucine,methionine, praline, serine, threonine, valine, tryptophan, or tyrosine.

As used herein, a range of carbon atoms which includes C₀ means thatcarbon is absent and is replaced with H (or deuterium). Thus, a range ofcarbon atoms which is C₀-C₆ includes carbons atoms of 1, 2, 3, 4, 5 and6 and for C₀, H (or deuterium)stands in place of carbon.

As used herein, the term “unsubstituted” means substituted only withhydrogen atoms.

As used herein, the term “substituted” or “optionally substituted” meansindependently (i.e., where more than a single substitution occurs, eachsubstituent is independent of another substituent) one or moresubstituents (independently up to five substituents, preferably up tothree substituents, often 1 or 2 substituents on a moiety in a compoundaccording to the present invention, and may include substituents whichthemselves may be further substituted) at a carbon (or nitrogen)position anywhere on a molecule within context, and includes assubstituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO₂),halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl,especially a methyl group such as a trifluoromethyl), an alkyl group(preferably, C₁-C₁₀, more preferably, C₁-C₆), aryl (especially phenyland substituted phenyl for example benzyl or benzoyl), alkoxy group(preferably, C₁-C₆ alkyl or aryl, including phenyl and substitutedphenyl), thioether (C₁-C₆ alkyl or aryl), acyl (preferably, C₁-C₆ acyl),ester or thioester (preferably, C₁-C₆ alkyl or aryl) including alkyleneester (such that attachment is on the alkylene group, rather than at theester function which is preferably substituted with a C₁-C₆ alkyl oraryl group), preferably, C₁-C₆ alkyl or aryl, halogen (preferably, F orCl), amine (including a five- or six-membered cyclic alkylene amine,further including a C₁-C₆ alkyl amine or a C₁-C₆ dialkyl amine whichalkyl groups may be substituted with one or two hydroxyl groups) or anoptionally substituted N(C₀-C₆ alkyl)C(O)(OC₁-C₆ alkyl) group (which maybe optionally substituted with a polyethylene glycol chain to which isfurther bound an alkyl group containing a single halogen, preferablychlorine substituent), hydrazine, amido, which is preferably substitutedwith one or two C₁-C₆ alkyl groups (including a carboxamide which isoptionally substituted with one or two C₁-C₆ alkyl groups), alkanol(preferably, C₁-C₆ alkyl or aryl), or alkanoic acid (preferably, C₁-C₆alkyl or aryl). Substituents according to the present invention mayinclude, for example SiR₁R₂R₃ groups wherein each of R₁ and R₂ is asotherwise described herein, and R₃ is H or a C₁-C₆ alkyl group,preferably R₁, R₂, R₃ in this context is a C₁-C₃ alkyl group (includingan isopropyl or t-butyl group). Each of the above-described groups maybe linked directly to the substituted moiety or alternatively, thesubstituent may be linked to the substituted moiety (preferably in thecase of an aryl or heteroaryl moiety) through an optionally substituted—(CH₂)_(m)— or, alternatively, an optionally substituted —(OCH₂)_(m)—,—(OCH₂CH₂)_(m)— or —(CH₂CH₂O)_(m)— group, which may be substituted withany one or more of the above described substituents. Alkylene groups—(CH₂)_(m)— or —(CH₂)_(n)— groups or other chains such as ethyleneglycol chains, as identified above, may be substituted anywhere on thechain.

Preferred substituents on alkylene groups include halogen or C₁-C₆(preferably C₁-C₃) alkyl groups, which may be optionally substitutedwith one or two hydroxyl groups, one or two ether groups (O—C₁-C₆groups), up to three halo groups (preferably F), or a sidechain of anamino acid as otherwise described herein and optionally substitutedamide (preferably carboxamide substituted as described above) orurethane groups (often with one or two C₀-C₆ alkyl substituents, whichgroup(s) may be further substituted). In certain embodiments, thealkylene group (often a single methylene group) is substituted with oneor two optionally substituted C₁-C₆ alkyl groups, preferably C₁-C₄ alkylgroup, most often methyl or O-methyl groups or a sidechain of an aminoacid as otherwise described herein. In the present invention, a moietyin a molecule may be optionally substituted with up to fivesubstituents, preferably up to three substituents. Most often, in thepresent invention moieties which are substituted are substituted withone or two substituents.

As used herein, the term “substituted” (each substituent beingindependent of any other substituent) also means within its context ofuse C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, amido, carboxamido, sulfone,including sulfonamide, keto, carboxy, C₁-C₆ ester (oxy ester or carbonylester), C₁-C₆ keto, urethane —O—C(O)—NR₁R₂ or —N(R₁)—C(O)—O—R₁, nitro,cyano and amine (especially including a C₁-C₆ alkylene —NR₁R₂, a mono-or di-C₁-C₆ alkyl substituted amines which may be optionally substitutedwith one or two hydroxyl groups). Each of these groups contains unlessotherwise indicated, within context, between 1 and 6 carbon atoms. Incertain embodiments, preferred substituents will include, for example,NH, NHC(O), 0, =0, (CH₂)_(m) (here, m and n are in context, 1, 2, 3, 4,5 or 6), S, S(O), SO₂ or NHC(O)NH, (CH₂)_(n)OH, (CH₂)_(n)SH,(CH₂)_(n)COOH, C₁-C₆ alkyl, (CH₂)_(n)O(C₁-C₆ alkyl), (CH₂)_(n)C(O)(C₁-C₆alkyl), (CH₂)_(n)OC(O)(C₁-C₆ alkyl), (CH₂)_(n)C(O)O(C₁-C₆ alkyl),(CH₂)_(n)NHC(O)R₁, (CH₂)_(n)C(O)NR₁R², (OCH₂)_(n)OH, (CH₂O)_(n)COOH,C₁-C₆ alkyl, (OCH₂)_(n)O(C₁-C₆ alkyl), (CH₂O)_(n)C(O)(C₁-C₆ alkyl),(OCH₂)_(n)NHC(O)R₁, (CH₂O)_(n)C(O)NR₁R², S(O)₂R_(s), S(O)R_(s) (R_(s) isC₁-C₆ alkyl or a (CH₂)_(m)NR₁R₂ group), NO₂, CN, or halogen (F, Cl, Br,I, preferably F or Cl), depending on the context of the use of thesubstituent. R₁ and R₂ are each, within context, H or a C₁-C₆ alkylgroup (which may be optionally substituted with one or two hydroxylgroups or up to three halogen groups, preferably fluorine).

The term “substituted” also means, within the chemical context of thecompound defined and substituent used, an optionally substituted aryl orheteroaryl group or an optionally substituted heterocyclic group asotherwise described herein. Alkylene groups may also be substituted asotherwise disclosed herein, preferably with optionally substituted C₁-C₆alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl ispreferred, thus providing a chiral center), a sidechain of an amino acidgroup as otherwise described herein, an amido group as describedhereinabove, or a urethane group OC(O)NR₁R₂ group wherein R₁ and R₂ areas otherwise described herein, although numerous other groups may alsobe used as substituents. Various optionally substituted moieties may besubstituted with 3 or more substituents, preferably no more than 3substituents and preferably with 1 or 2 substituents. It is noted thatin instances where, in a compound at a particular position of themolecule substitution is required (principally, because of valency), butno substitution is indicated, then that substituent is construed orunderstood to be H, unless the context of the substitution suggestsotherwise.

As used herein, the terms “aryl” and “aromatic,” in context, refer to asubstituted (as otherwise described herein) or unsubstituted monovalentaromatic radical having a single ring (e.g., benzene, phenyl, benzyl) orcondensed rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) andcan be bound to the compound according to the present invention at anyavailable stable position on the ring(s) or as otherwise indicated inthe chemical structure presented. Other examples of aryl groups, incontext, may include heterocyclic aromatic ring systems “heteroaryl”groups having one or more nitrogen, oxygen, or sulfur atoms in the ring(monocyclic) such as imidazole, furyl, pyrrole, furanyl, thiene,thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fusedring systems such as indole, quinoline, indolizine, azaindolizine,benzofurazan, etc., among others, which may be optionally substituted asdescribed above. Among the heteroaryl groups which may be mentionedinclude nitrogen-containing heteroaryl groups such as pyrrole, pyridine,pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole,triazole, triazine, tetrazole, indole, isoindole, indolizine,azaindolizine, purine, indazole, quinoline, dihydroquinoline,tetrahydroquinoline, isoquinoline, dihydroisoquinoline,tetrahydroiso-quinoline, quinolizine, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine,imidazotriazine, pyrazinopyridazine, acridine, phenanthridine,carbazole, carbazoline, perimidine, phenanthroline, phenacene,oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine andpyridopyrimidine; sulfur containing aromatic heterocycles such asthiophene and benzothiophene; oxygen containing aromatic heterocyclessuch as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; andaromatic heterocycles comprising 2 or more hetero atoms selected fromamong nitrogen, sulfur and oxygen, such as thiazole, thiadizole,isothiazole, benzoxazole, benzothiazole, benzothiadiazole,phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine,furopyrimidine, thienopyrimidine and oxazole, among others, all of whichmay be optionally substituted.

As used herein, the term “substituted aryl” refers to an aromaticcarbocyclic group comprised of at least one aromatic ring or of multiplecondensed rings at least one of which being aromatic, wherein thering(s) are substituted with one or more substituents. For example, anaryl group can comprise a substituent(s) selected from: (CH₂)_(n)OH,(CH₂)_(n)O(C₁-C₆)alkyl, (CH₂)_(n)O(CH₂)_(n)(C₁-C₆)alkyl,(CH₂)_(n)C(O)(C₀-C₆) alkyl, (CH₂)_(n)C(O)O(C₀-C₆) alkyl,(CH₂)_(n)OC(O)(C₀-C₆) alkyl, amine, mono- or di-(C₁-C₆ alkyl) aminewherein the alkyl group on the amine is optionally substituted with 1 or2 hydroxyl groups or up to three halo (preferably F, Cl) groups, OH,COOH, C₁-C₆ alkyl, preferably CH₃, CF₃, OMe, OCF₃, NO₂, or CN group(each of which may be substituted in ortho-, meta- and/or para-positionsof the phenyl ring, preferably para-), an optionally substituted phenylgroup (the phenyl group itself is preferably substituted with a linkergroup attached to a ARB group, including a E3LB group), and/or at leastone of F, Cl, OH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (inortho-, meta- and/or para-positions of the phenyl ring, preferablypara-), a naphthyl group, which may be optionally substituted, anoptionally substituted heteroaryl, preferably an optionally substitutedisoxazole including a methyl substituted isoxazole, an optionallysubstituted oxazole including a methyl substituted oxazole, anoptionally substituted thiazole including a methyl substituted thiazole,an optionally substituted isothiazole including a methyl substitutedisothiazole, an optionally substituted pyrrole including a methylsubstituted pyrrole, an optionally substituted imidazole including amethyl imidazole, an optionally substituted benzimidazole ormethoxybenzyl-imidazole, an optionally substituted oximidazole ormethyloximidazole, an optionally substituted diazole group, including amethyldiazole group, an optionally substituted triazole group, includinga methyl substituted triazole group, an optionally substituted pyridinegroup, including a halo (preferably, F) or methyl substituted pyridinegroup or an oxapyridine group (where the pyridine group is linked to thephenyl group by an oxygen), an optionally substituted furan, anoptionally substituted benzofuran, an optionally substituteddihydrobenzofuran, an optionally substituted indole, indolizine orazaindolizine (2, 3, or 4-azaindolizine), an optionally substitutedquinoline, and combinations thereof.

As used herein, the term “carboxyl” denotes the group C(O)OR, wherein Ris hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl, whereas these generic substituentshave meanings which are identical with definitions of the correspondinggroups defined herein.

As used herein, the terms “heteroaryl” and “hetaryl” include, withoutlimitation, an optionally substituted quinoline (which may be attachedto the pharmacophore or substituted on any carbon atom within thequinoline ring), an optionally substituted indole (includingdihydroindole), an optionally substituted indolizine, an optionallysubstituted azaindolizine (2, 3 or 4-azaindolizine) an optionallysubstituted benzimidazole, benzodiazole, benzoxofuran, an optionallysubstituted imidazole, an optionally substituted isoxazole, anoptionally substituted oxazole (preferably methyl substituted), anoptionally substituted diazole, an optionally substituted triazole, atetrazole, an optionally substituted benzofuran, an optionallysubstituted thiophene, an optionally substituted thiazole (preferablymethyl and/or thiol substituted), an optionally substituted isothiazole,an optionally substituted triazole (preferably a 1,2,3-triazolesubstituted with a methyl group, a triisopropylsilyl group, anoptionally substituted (CH₂)_(m)OC₁-C₆ alkyl group or an optionallysubstituted (CH₂)_(m)C(O)OC₁-C₆ alkyl group), an optionally substitutedpyridine (2-, 3-, or 4-pyridine) or a group according to the chemicalstructure:

-   -   wherein S^(C) is CHR^(SS), NR^(URE), or O;    -   R^(HET) is H, CN, NO₂, halo (preferable Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a), wherein        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl).    -   R^(SS) is H, CN, NO₂, halo (preferably F or Cl), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups), optionally        substituted O—(C₁-C₆ alkyl) (preferably substituted with one or        two hydroxyl groups or up to three halo groups) or an optionally        substituted —C(O)(C₁-C₆ alkyl) (preferably substituted with one        or two hydroxyl groups or up to three halo groups);    -   R^(URE) is H, a C₁-C₆ alkyl (preferably H or C₁-C₃ alkyl) or a        —C(O)(C₁-C₆ alkyl), each of which groups is optionally        substituted with one or two hydroxyl groups or up to three        halogen, preferably fluorine groups, or an optionally        substituted phenyl group, an optionally substituted heterocycle,        for example piperidine, morpholine, pyrrolidine,        tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine,        each of which is optionally substituted, and    -   Y^(C) is N or C—R^(YC), wherein R^(YC) is H, OH, CN, NO₂, halo        (preferably Cl or F), optionally substituted C₁-C₆ alkyl        (preferably substituted with one or two hydroxyl groups or up to        three halo groups (e.g. CF₃), optionally substituted O(C₁-C₆        alkyl) (preferably substituted with one or two hydroxyl groups        or up to three halo groups) or an optionally substituted        acetylenic group —C≡C—R_(a), wherein R_(a) is H or a C₁-C₆ alkyl        group (preferably C₁-C₃ alkyl).

R^(PRO) is H, optionally substituted C₀-C₆ alkyl or an optionallysubstituted aryl, heteroaryl or heterocyclic group selected from thegroup consisting of oxazole, isoxazole, thiazole, isothiazole,imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene,pyridine, piperidine, piperazine, morpholine, quinoline (each preferablysubstituted with a C₀-C₃ alkyl group, preferably methyl or a halo grouppreferably F or Cl), benzofuran, indolem indolizine, azaindolizine:R^(PRO1) and R_(PRO2) are each independently H, an optionallysubstituted C₀-C₃ alkyl group or together form a keto group and each nis independently 0,1,2,3,4,5 or 6 or an optionally substitutedheterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine,piperazine or morpholine (each of which groups when substituted arepreferably substituted with a methyl or halo).

As used herein, the terms “arylkyl” and “heteroarylalkyl” refer togroups that comprise both aryl or, respectively, heteroaryl as well asalkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ringsystems according to the above definitions.

As used herein, the term “arylalkyl” as used herein refers to an arylgroup as defined above appended to an alkyl group defined above. Thearylalkyl group is attached to the parent moiety through an alkyl groupwherein the alkyl group is one to six carbon atoms. The aryl group inthe arylalkyl group may be substituted as defined above.

As used herein, the terms “heterocycle” and “heterocyclic” refer to acyclic group which contains at least one heteroatom, i.e., O, N or S,and may be aromatic (heteroaryl) or non-aromatic. Thus, the heteroarylmoieties are subsumed under the definition of heterocycle, depending onthe context of its use. Exemplary heterocycles include: azetidinyl,benzimidazolyl 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl,benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl,dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane,1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl,imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl,isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl,naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone,pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide,succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl,tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, and thiane amongothers.

Heterocyclic groups can be optionally substituted with a member selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, -SOaryl, —SO-heteroaryl,—SO₂-alkyl, -SO₂-substituted alkyl, —SO₂-aryl, oxo (═O), and—SO₂-heteroaryl. Such heterocyclic groups can have a single ring ormultiple condensed rings. Examples of nitrogen heterocycles andheteroaryls include, but are not limited to, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,isoindole, indole, indazole, purine, quinolizine, isoquinoline,quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline,cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like aswell as N-alkoxynitrogen containing heterocycles. The term“heterocyclic” also includes bicyclic groups in which any of theheterocyclic rings is fused to a benzene ring or a cyclohexane ring oranother heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, and the like).

As used herein, the term “cycloalkyl” includes, without limitation,univalent groups derived from monocyclic or polycyclic alkyl groups orcycloalkanes, as defined herein, e.g., saturated monocyclic hydrocarbongroups having from three to twenty carbon atoms in the ring, including,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like.

As used herein, the term “substituted cycloalkyl” includes, withoutlimitation, a monocyclic or polycyclic alkyl group being substituted byone or more substituents, for example, amino, halogen, alkyl,substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, orsulfa, whereas these generic substituent groups have meanings which areidentical with definitions of the corresponding groups as definedherein.

As used herein, the term “heterocycloalkyl” refers to a monocyclic orpolycyclic alkyl group in which at least one ring carbon atom of itscyclic structure being replaced with a heteroatom selected from thegroup consisting of N, O, S, or P.

As used herein, the term “substituted heterocycloalkyl” refers to amonocyclic or polycyclic alkyl group in which at least one ring carbonatom of its cyclic structure being replaced with a heteroatom selectedfrom the group consisting of N, O, S, or P, and the group contains oneor more substituents selected from the group consisting of halogen,alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro,mercapto, or sulfa, whereas these generic substituent group havemeanings which are identical with definitions of the correspondinggroups as defined herein.

EXAMPLES

Unless otherwise noted, starting materials, reagents, and solvents wereobtained from commercial suppliers (e.g. Acros Organics, Sigma-Aldrich,Alfa Aesar, Fluorochem, and Merck) and were used without furtherpurification. Reactions were routinely monitored by thin-layerchromatography (TLC) performed on silica gel 60 F₂₅₄ (layer 0.2 mm)pre-coated aluminium foil (with fluorescent indicator UV254)(Sigma-Aldrich). Developed plates were air-dried and visualized under UVlight (254/365 nm) or by using KMnO₄ or ninhydrin solutions. Flashcolumn chromatography was performed on Merck silica gel 60 (mesh230-400).

¹H NMR and ¹³C NMR spectra were recorded at room temperature at 400 and101 MHz, respectively, on a Bruker Avance 400 spectrometer by using TMSor residual solvent peak as internal standard. Chemical shifts arereported in ppm (δ) and the coupling constants (J) are given in Hertz(Hz). Peak multiplicities are abbreviated as follow: s (singlet), bs(broad singlet), d (doublet), dd (double doublet), t (triplet), dt(double triplet), q (quartet), p (pentet), and m (multiplet).

High-Resolution Mass Spectroscopy (HRMS) spectra were registered onAgilent Technologies 6540 UHD Accurate Mass Q-TOF LC-MS system. Thepurity of all final compounds that were evaluated in biological assayswas assessed as >95%, using LC-MS. The analyses were carried outaccording to the method listed below. The mobile phase was a mixture ofwater (solvent A) and acetonitrile (solvent B), both containing formicacid at 0.1%. Method: Acquity UPLC BEH C18 1.7 μm (C18, 150×2.1 mm)column at 40° C. using a flow rate of 0.65 mL/min in a 10 min gradientelution. Gradient elution was as follows: 99.5:0.5 (A/B) to 5:95 (A/B)over 8 min, 5:95 (A/B) for 2 min, and then reversion back to 99.5:0.5(A/B) over 0.1 min. The UV detection is an averaged signal fromwavelength of 190 nm to 640 nm and mass spectra are recorded on a massspectrometer using positive mode electro spray ionization. The chemicalnames were generated using ChemBioDraw 12.0 from CambridgeSoft.

Compounds described herein may be synthesized as described herein, usingmodified methods described herein or by methods known to a person ofskill in the art.

Chemistry abbreviations: ACN, acetonitrile; AcOH, acetic acid; AcOK,potassium acetate; Boc, tert-butoxycarbonyl; CD₃OD, deuterated methanol;CDCl₃, deuterated chloroform; DCE, dichloroethane; DCM, dichloromethane;DEE, diethyl ether; DIAD, diisopropyl azodicarboxylate; DIPEA,N,N′-diisopropylethylamine; DMA, dimethylacetamide; DMF,dimethylformamide; DMSO, dimethylsulfoxide; DMSO-d₆, deuterateddimethylsulfoxide; EA, ethyl acetate; h, hour; EDC,1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; Et₃N, triethylamine;HATU, 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; min, minutes; HOBt, 1-hydroxybenzotriazole; HIRMS,high-resolution mass spectroscopy; MeOH, methanol; NMR, nuclear magneticresonance; tBu, tert-butyl; THF, tetrahydrofuran; TLC, thin-layerchromatography; TMS, tetramethylsilane; PE, petroleum ether; rt, roomtemperature.

Chemical Synthesis

Compounds of general formula (I) may be prepared by the generalsynthetic approaches described below (General Scheme 1 and 2), togetherwith synthetic methods known in the art of organic chemistry. In allmethods, it is well-understood that protecting groups for sensitive orreactive groups may be employed where necessary in accordance withgeneral principles of chemistry. Protecting groups are manipulatedaccording to standard methods of organic synthesis (T. W. Green and P.G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3′ edition,John Wiley & Sons). These groups are removed at a convenient stage ofthe compound synthesis using methods that are readily apparent to thoseskilled in the art. The selection of processes as well as the reactionconditions and order of their execution shall be consistent with thepreparation of compounds of Formula (I). Specific detailed syntheticprocedures for a variety of intermediates and final compounds within thescope of the present disclosure is publicly available in the U.S. PatentApplication Publication of U.S. patent application Ser. No. 16/777,294,filed on Jan. 30, 2020, as well as its PCT counterpart, which arepublishing on or about Jul. 30, 2020.

ARB: Androgen Receptor (AR) Binder; E3LB: E3 Ligase Binder.

General Procedure III: HATU-Mediated Amidation Reaction.

2-(2,3-Difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide(Example 1)

In an oven-dried round-bottom flask, under nitrogen atmosphere, to astirred solution of2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.048 g, 0.122 mmol, 1.0 equiv),4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (L) (0.050 g, 0.122 mmol, 1.0 equiv), and DIPEA (0.083 mL,0.489 mmol, 4.0 equiv) in dry DMF (3.0 mL) was added HATU (0.058 g,0.153 mmol, 1.25 equiv). Stirring was continued at rt for 16h. Thereaction mixture was diluted with water (30 mL) and extracted with EA(15 mL×3). The reunited organic layers were washed with water (20 mL×3),brine (20 mL×3), dried over anhydrous Na₂SO₄ and then concentrated underreduced pressure to give a crude residue, which was purified by flashcolumn chromatography on SiO₂ (DCM/Acetone/MeOH, 90:10:0 to 89:10:1)affording a yellow solid (0.015 g, 18% yield). ¹H NMR (400 MHz, CDCl₃):δ 8.09 (s, 1H), 7.63-7.56 (m, 1H), 7.56-7.48 (m, 1H), 7.11 (d, J=7.0 Hz,1H), 7.05 (s, 1H), 7.04-6.96 (m, 1H), 6.93 (s, 1H), 6.90 (d, J=8.5 Hz,1H), 6.25 (s, 1H), 4.93 (dd, J=5.3, 11.9 Hz, 1H), 4.60 (s, 2H),3.89-3.78 (m, 4H), 3.64-3.51 (m, 4H), 3.36 (q, J=6.8 Hz, 2H), 3.33-3.26(m, 2H), 2.97-2.68 (m, 3H), 2.18-2.11 (m, 1H), 1.79-1.35 (m, 8H); ¹³CNMR (101 MHz, CDCl₃): δ 170.87, 170.74, 169.50, 168.25, 167.92, 167.59,150.76 (dd, J=11.6, 251.4 Hz), 146.96, 146.37-146.09 (m), 144.62 (dd,J=1.5, 9.1 Hz), 144.15 (dd, J=14.0, 247.3 Hz), 136.15, 132.48, 125.04,124.53 (dd, J=4.0, 7.8 Hz), 116.63, 112.43 (d, J=17.2 Hz), 111.46,109.90, 105.96, 72.42 (d, J=4.9 Hz), 66.11 (2C), 48.87, 48.62 (2C),42.52, 38.95, 31.41, 29.42, 29.13, 26.62, 26.55, 22.82. HRMS (ESI) m/z[M+H]+ calcd for C₃₄H₃₆F₂N₆O₇S 711.2407, found 711.2412.

(2S,4R)-1-((S)-2-(5-(2-(2,3-Difluoro-6-(2-morpholinothiazol-4yl)phenoxy)acetamido)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(Example 16)

General Procedure III (4 hours) was followed by using(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E)(0.67 g, 1.71 mmol),(2S,4R)-1-((S)-2-(5-aminopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2carboxamide hydrochloride (AZ) (0.99 g, 1.71 mmol), DIPEA (1.19 mL, 6.82mmol), and HATU (0.81 g, 2.13 mmol) in dry DMF (7.5 mL) to afford thetitled compound as white solid (0.604 g, 40% yield) followingpurification by flash column chromatography on SiO₂ (DCM/Acetone/MeOH,60:37:3). ¹H NMR (400 MHz, CDCl₃): δ 8.70 (s, 1H), 7.60 (ddd, J=8.5,6.0, 2.1 Hz, 1H), 7.48-7.34 (m, 5H), 7.12 (t, J=5.6 Hz, 1H), 7.05-6.92(m, 2H), 6.32 (d, J=8.6 Hz, 1H), 5.15-5.05 (m, 1H), 4.75 (t, J=8.0 Hz,1H), 4.66-4.53 (m, 3H), 4.49 (bs, 1H), 4.11 (d, J=11.4 Hz, 1H),3.90-3.80 (m, 4H), 3.59 (dd, J=11.4, 3.5 Hz, 1H), 3.55-3.46 (m, 4H),3.45-3.17 (m, 3H), 2.61-2.50 (m, 4H), 2.39-2.21 (m, 2H), 2.07 (dd,J=13.6, 8.3 Hz, 1H), 1.83-1.52 (m, 4H), 1.48 (d, J=6.9 Hz, 3H), 1.06 (s,9H); ¹³C NMR (101 MHz, CDCl₃): δ 173.34, 172.25, 170.85, 169.54, 168.31,150.64 (dd, J=251.3, 11.3 Hz), 150.26, 148.50, 146.40 (d, J=1.7 Hz),144.69-144.42 (m), 144.19 (dd, J=247.5, 14.0 Hz), 143.11, 131.58,130.88, 129.56 (2C), 126.41 (2C), 125.32 (d, J=3.4 Hz), 124.48 (dd,J=7.7, 3.9 Hz), 112.49 (d, J=17.1 Hz), 106.25, 72.29 (d, J=5.0 Hz),70.03, 66.13 (2C), 58.24, 57.67, 56.72, 48.86, 48.55 (2C), 38.35, 35.47,35.35, 34.92, 28.73, 26.51 (3C), 22.40, 22.24, 16.10. HRMS (ESI) m/z[M+H]+ calcd for C₄₃H₅₃F₂N₇O₇S₂ 882.34887, found 882.3458.

(S)-1-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide(Example 24)

To the solution of tert-butyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(((S)-1-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(BW) (0.060 g, 0.056 mmol) in dry DCM (0.5 mL) was added a solution of4N HCl in dioxane (0.5 mL) and the mixture was stirred at rt for 4 h.The solvent was evaporated to dryness and the residue was diluted withsaturated solution of NaHCO₃ (10 mL) and extracted with EA (6 mL×3). Thereunited organic phases were washed with brine (10 mL), dried overNa₂SO₄, and evaporated under reduced pressure affording a crude residuewhich was purified by flash column chromatography on SiO₂ (DCM/MeOH,95:5 to 94:6) yielding the titled compound (0.041 g, 75% yield) as whitesolid. HIRMS (ESI) m/z [M+Na]+ calcd for C₅₁H₆₅F₂N₇O₈S 996.44756, found996.44769.

(S)-1-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide(Example 25)

To the solution of tert-butyl((5)-1-(((5)-1-cyclohexyl-2-((5)-2-(((5)-1-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(BY) (0.035 g, 0.033 mmol) in dry DCM (0.3 mL) was added a solution of4N HCl in dioxane (0.3 mL) and the mixture was stirred at rt for 4 h.The solvent was evaporated to dryness and the residue was diluted withsaturated solution of NaHCO₃ (10 mL) and extracted with EA (5 mL×3). Thereunited organic phases were washed with brine (10 mL), dried overNa₂SO₄, and evaporated under reduced pressure affording a crude residuewhich was purified by flash column chromatography on SiO₂ (DCM/MeOH,93:7 to 9:1) yielding the titled compound (0.010 g, 33% yield) as whitesolid. HIRMS (ESI) m/z [M+Na]+ calcd for C₅₁H₆₄F₂N₈O₇S 993.44789, found993.44843.

(S)-1-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide(Example 26)

To the solution of tert-butyl((S)-1-(((S)-1-cyclohexyl-2-((5)-2-(((5)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(BZ) (0.030 g, 0.027 mmol) in dry DCM (0.3 mL) was added a solution of4N HCl in dioxane (0.3 mL) and the mixture was stirred at rt for 4 h.The solvent was evaporated to dryness and the residue was diluted withsaturated solution of NaHCO₃ (10 mL) and extracted with EA (5 mL×3). Thereunited organic phases were washed with brine (10 mL), dried overNa₂SO₄, and evaporated under reduced pressure affording a crude residuewhich was purified by flash column chromatography on SiO₂ (DCM/MeOH,95:5 to 93:7) yielding the titled compound (0.017 g, 63% yield) as whitesolid. IRMS (ESI) m/z [M+H]+ calcd for C₅₃H₆₈F₂N₈O₇S 999.49725, found999.49979.

Experimental Example 1: 22Rv1 Cell Proliferation Assays

The human prostate cancer cell line, 22Rv1 has been reported to expressa high level of AR-V7. Thus, 22Rv1 was seeded at 50,000 cells/well on a24-well plate in quadruplicates and treated with test compound inconcentrations ranging up to 20 μM for four days. Standard culture mediawas RPMI-1640 supplemented with 10% fetal bovine serum. The testcompound initially was dissolved in DMSO at 50 mM. This stock solutionwas then diluted as needed for the indicated concentrations. At the endof the four-day period, cells were harvested using 1% trypsin andcounted using an automated cell counter.

The results as shown in Table 1 below demonstrate that the testcompounds decreased cell count in a concentration dependent manner. Inthe Table: (+)—the cell count decreased between 0 and 20%; (++)—the cellcount decreased less than 50%; (+++)—the cell count decreased by morethan 50%.

TABLE 1 Compound 22Rv1 cell count decrease of Example at 10 μM for 48hours 1 ++ 2 + 3 ++ 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 + 12 + 13 + 14 + 15++ 16 ++ 17 ++ 18 ++ 19 ++ 20 ++ 21 ++ 22 + 23 + 24 +++ 25 +++ 26 +++ 27+++ 28 +++ 29 ++ 30 ++ 31 +++ 32 + 33 + 34 ++ 35 +++ 36 +++

Experimental Example 2: Immunoblot

Immunoblot was carried out to determine the effect of the test compoundon AR-V7. 22Rv1 was plated at 200,000 cell/well on a 6-well plate andcultured as described with 10 μM test compound. After four days oftreatment, cells were harvested using a cell scraper and lysed in astandard fashion using SDS. After removing debris via centrifuge, 30 μgof protein were loaded onto SDS-PAGE gel. After electrophoresis, proteinwas transferred to a nylon membrane and ECL was carried out usingprimary antibody against AR-V7 (Thermofisher Scientific, cat#NC0752138). Protein bands were visualized using the commerciallyavailable Enhanced Chemiluminescence (ECL) kit (Thermofisher). As shownin FIG. 1 , the results demonstrated a dramatically decreased level ofAR-V7 protein.

Experimental Example 3

Compounds according to the present disclosure (“Test Compound”) aretested for in vitro efficacy against various CaP cell lines.

Cell Culture. Human CaP cell lines, LNCaP, 22Rv1, VCaP, PC3, and DU145are obtained from the American Type Culture Collection (ATCC) andmaintained in the standard culture media: RPMI-1640 supplemented with10% fetal bovine serum (FBS). LNCaP, 22Rv1, and VCaP areandrogen-responsive cell lines, while PC3 and DU145 are not. Toestablish SAT resistant CaP cell lines, LNCaP, 22Rv1, and VCaP aretreated continuously with 10-50 μM abiraterone, apalutamide,darolutamide, or enzalutamide. After 3-6 months, stable cell lines areestablished and designated as LNCaP-Abi^(R), LNCaP-Apa^(R),LNCaP-Daro^(R), LNCaP-Enz^(R), VCaP-Abi^(R), VCaP-Apa^(R),VCaP-Daro^(R), VCaP-Enz^(R), 22Rv1-Abi^(R), 22Rv1-Apa^(R),22Rv1-Daro^(R), and 22Rv1-Enz^(R). Unless otherwise specified, thestandard culture media for these SAT-resistant cell lines included 10 μMof their respective SAT. For the proteasome inhibitor study, theinhibitors MG132 and Epoxomicin are used. The E3 ligase inhibitorsHeclin, Nutlin 3a, Thalidomide, and VH298 are used. Cell lines obtainedfrom ATCC are confirmed by checking their morphology using opticalmicroscopy, establishing baselines for cell proliferation, verifyingspecies of origin using isoenzymology, and characterizing the cell's DNAfingerprint using short tandem repeat (STR) profiling. Mycoplasmacontamination is also assessed using a PCR based detection system.

Apoptosis Assay. An apoptosis assay is carried out using the ThermoFisher ApoDETECT Annexin V-FITC kit following the protocol recommendedby the vendor. Briefly, after treatment with 1 μM of Test Compound for 3to 24 hours, cells are fixed with 80% ethanol and washed with PBS threetimes. Then, fixed cells are incubated with Annexin V-FITC in PBSsolution for 30 minutes at room temperature. After washing three timeswith PBS, cells are treated with 300 nM DAPI in PBS for 5 minutes atroom temperature. Finally, after washing three times with PBS, mountingsolution is added and the cells are visualized using immunofluorescencemicroscopy. Next, a TUNEL assay is performed using Promega DeadEndFluorometric TUNEL system. After treatment with Test Compound andfixation as described above in the Annexin-V experiment, 100 μl ofequilibration buffer is incubated for 10 min. Then, 50 μl of TdTreaction mix is added and incubated for 60 min at 37° C. in a humidifiedchamber. Finally, stop solution is added and samples are mounted onslides using mounting medium. To assess non-specific cytotoxicity, anLDH assay kit is used.

Transient Transfections. One μg of a plasmid containing cDNA of AR-V7 orAR-FL is transfected into indicated the CaP cell lines on 6-well plates.Three μl of lipofectamine 3000 is used for each transfection.

Immunoblot Analysis. CaP cells are collected and lysed with the lysisbuffer (20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM Na₂EDTA, 1 mM EGTA,1% Triton, 2.5 mM sodium pyrophosphate, 1 mM beta-glycerophosphate, 1 mMNa₃VO₄, and 1 μg/ml leupeptin) containing 1 mM phenylmethylsulfonylfluoride (PMSF). Cell lysates are then centrifuged and protein in thesupernatant is quantified. After separating 25-50 g of protein usingSDS-PAGE, samples are incubated with AR-V7, GR, PR, ERα, AR-FL,ubiquitin, or 3-actin antibodies. For AR-V7, AR-FL, PR, GR, and ERα,immunoblots, primary antibody is diluted 1:1000 in 5% skim milk. For the3-actin immunoblot, 1:10000 diluted primary antibody is used. Allmembranes are incubated overnight at 4° C. Following the incubation withappropriate secondary antibody, immunoblots are analyzed usingSuperSignal West Femto Maximum Sensitivity Substrate (ThermoFisher).

In Vivo Study. To explore the therapeutic potential of Test Compound,22Rv1, 22Rv1-Enz^(R), VCaP, and VCaP-Enz^(R) are injected into nu/nuimmunodeficient mice. When the resulting tumors reached an average sizeof 3 mm in diameter, all animals are surgically castrated via bilateralorchiectomy and divided into four groups of five mice each. Foranesthesia, 3% isofluorane gas inhalation is used. Tumor size wasmeasured using calipers and tumor volume was calculated using theformula: tumor volume=length×width²/0.361.

Mice are then treated daily with Test Compound with or withoutenzalutamide via the indicated route (intratumoral, intraperitoneal, ororal) for five to six weeks. At the end of the study, all animals aresacrificed and tumors are harvested and analyzed. Statisticalsignificance is calculated using the Student's t-test for pairedcomparisons of experimental groups and, where appropriate, by Wilcoxonrank sum test, and by 2-way ANOVA. In vitro experiments are repeated aminimum of three times.

Results. Treatment of the AR-V7-expressing CaP cell line 22Rv1 with theCompound of Example 16 (0, 0.01, 0.1, 1 and 10 μM) for 24 hours,immunoblot demonstrated decreased AR-V7 and AR-FL protein expressionlevels in 22Rv1 cells starting at concentration as low as 0.1 μM and 1μM, respectively. Example 16's effect on AR-V7 and AR-FL protein levelswas concentration-dependent and AR-specific, as there was no visibleeffect on the expression levels of the proteins glucocorticoid receptor(GR), progesterone receptor (PR) a and b, and estrogen receptor alpha(ER). The concentration of Compound of Example 16 at which 50% of AR-V7and AR-FL degraded in 24 hours (DC₅₀) is determined to be 0.37 and 2 μM,respectively. These results demonstrate that the Compound is able todegrade both AR-V7 and AR-FL, although the degradation effect is moreefficient against AR-V7 compared to AR-FL.

Along with degrading AR-V7 and AR-FL, in the cell proliferation assay,Compound of Example 16 decreased the cell count of 22Rv1 in aconcentration dependent manner over 6 days (cell counts areapproximately 90%, 70% and 65% of control at 0.01, 0.1 and 1 μM,respectively). As additional controls, constructs comprising Example16's DBD binding motif with its linker (Control 1, C1) and Example 16'sVHL domain with its linker (Control 2, C2) are prepared, as shown below:

Treatment with C1 or C2 does not result in any significant changes incell count at up to 1 μM concentration compared to the control (cellcounts are 95-105% of control cell counts).

In another set of experiments, several cell lines (22Rv1, PC3, DU145,LNCaP, VCaP) are compared side to side for the effect of the Compound ofExample 16. At 1 μM of Compound of Example 16, 22Rv1 cell count isapproximately 40% of the control. The Compound only inhibits theproliferation of androgen-responsive cells (22Rv1, LNCaP, and VCaP). TheAR-negative cell lines, PC3 and DU145, are not affected by the Compound.Upon transfecting AR-V7 or AR-FL into 22Rv1 cells, there is seen apartial resistance to the Compound's inhibitory effect (at 1 μM).However, with the transfection of both AR-V7 and AR-FL, the Compound'seffect was completely abrogated in 22Rv1 cells. These results suggestthat the Compound of Example 16 inhibits CaP cellular proliferation bydegrading AR-V7 and AR-FL.

After treating 22Rv1 cells with Compound 16 at 1 μM, the annexin-V assayis carried out to assess the effect on apoptosis over a 0 to 48 hoursperiod. Starting approximately three hours after treatment, an increasein annexin-V staining is observed via fluorescence microscopy, and itcontinues to increase through 48 hours. This result is confirmed by theTUNEL assay. As a negative control, the C1 control is compared, and nochange in apoptosis is observed. In addition, using the lactatedehydrogenase (LDH) assay it is observed that the Compound at up to 20μM had no non-specific cytotoxic effect in 22Rv1 after six daystreatment (0.01, 0.1, 1 10 and 20 μM tested).

To determine the mechanism of the cell proliferation inhibition, 22Rv1cells are pretreated for 2 hours with the proteasome inhibitors MG-132(5 μM) and epoxomicin (1 μM) prior to treatment with Compound of Example16 at 1 μM. It is found that AR-V7 degradation is completely blocked, asshown by immunoblotting. The E3 ubiquitin ligase inhibitors are alsoexamined: VH 298 (VHL inhibitor; 20 μM), heclin (HECT inhibitor; 10 μM),nutlin 3a (MDM2 inhibitor; 0.1 μM), and thalidomide (cereblon inhibitor;10 μM). It is found that when 22Rv1 cells are pretreated with each ofthese inhibitors for two hours prior to incubation with 1 μM Compound ofExample 16, only VH298 pretreatment inhibits AR-V7 degradation.

To determine the ubiquitination status of AR proteins, 22Rv1 ispretreated with MG132 for two hours prior to adding Compound of Example16 (at 1 μM). Immunoblot analysis demonstrates polyubiquitination ofAR-V7 starting at 6 hours after Compound treatment. AR-FLpolyubiquitination is also detected, but occurs significantly later, at24 hours after treatment. Collectively, these results suggest that theCompound of Example 16 stimulates AR-V7 and AR-FL ubiquitination anddegradation specifically via the VHL E3 ligase/proteasome axis.

To assess the potential therapeutic role of the Compound, twelve humanCaP cell lines are generated that are resistant to the four FDA-approvedSAT agents: abiraterone, apalutamide, enzalutamide, and darolutamide.Specifically, LNCaP, VCaP, and 22Rv1 cells are cultured with each of theSAT agents for three to six months until resistance emerges. Theresulting cells are designated LNCaP-Abi^(R), LNCaP-Apal^(R),LNCaP-Darol^(R), LNCaP-Enz^(R), VcaP-Abi^(R), VcaP-Apal^(R),VcaP-Darol^(R), VcaP-Enz^(R), 22Rv1-Abi^(R), 22Rv1-Apal^(R),22Rv1-Darol^(R), and 22Rv1-Enz^(R). Quantitative PCR demonstrates thatall twelve SAT-resistant CaP cell lines express decreased and increasedmRNA and protein levels of AR-FL and AR-V7, respectively. Using the cellproliferation assay above, it is found that all twelve cell lines' cellcounts decreased after treatment with the Compound of Example 16 at 1 μMfor 6 days (cell counts were reduced generally to 6-80% of control forall lines, except 22Rv1-EnzR, which was decreased to about 45% ofcontrol). Immunoblot assays with 22Rv1, VCaP and LNCaP cells demonstratethat the Compound decreases the protein expression levels of both AR-V7and AR-FL in the parental and SAT-resistant cells. In all three celllines, the effect on the protein levels of AR-V7 is greater than that onAR-FL. As negative controls, the AR-negative PC3 and DU145 cells arealso compared. As predicted based on the suspected mechanism of action,the Compound had no major effect on the mRNA levels of AR-FL and AR-V7in these cells.

The in vivo effects of the Compound of Example 16 is assessed in miceusing enzalutamide-resistant CaP xenografts. First, 22Rv1-Enz^(R) tumorxenografts are established in nu/nu mice. Upon CaP xenograft formation(average diameter of 3 mm), mice are randomized into controls ortreatment. Control mice are treated with 100 μl vehicle containing 10mg/ml enzalutamide (n=5). The treatment group is injected with 100 μlvehicle containing 2.5 mg/ml Compound of Example 16 and 10 mg/mlenzalutamide daily directly into tumors (n=5) and tumor volumes werefollowed. The results demonstrate that mice treated with the Compoundhave a significantly smaller tumor volume at the end of 5 weeks(approximately 500 mm³ for treatment, and 800 mm³ for control). Duringthe treatment period, weight of the mice did not significantly change,suggesting that the Compound does not have major toxicity in mice.Tumors are harvested and analyzed at the end of the study period. It isfound that immunoblot demonstrates a significant decrease in AR-V7 andAR-FL protein levels in all treated tumors. Similar results are obtainedwhen the Compound of Example 16 is injected intratumorally intoVCaP-Enz^(R) xenografts.

To test whether the Compound is active systemically, an identical studyis carried out as above except for delivering the Compoundintraperitoneally (TP) or orally for four weeks. Enzalutamide-resistantCaP tumor xenografts are established in twelve mice and three each areassigned to the following four groups: control IP (vehicle), controloral (vehicle), 8.3 mg/kg IP, and 8.3 mg/kg oral. Because these cellsare resistant to enzalutamide, all animals are administeredenzalutamide. The results demonstrate that the Compound is effectivewhen administered IP (tumor size approximately 1000 mm³ for treatmentgroup, and 2200 mm³ for control group). Again, no significant change inweight was detected following treatment. Immunoblot shows that IPadministration of the Compound decreased AR-V7 and AR-FL proteinexpression in Enz^(R) Cap tumors. Similar results are found when theCompound is delivered orally (PO) (tumor size approximately 700 mm³ fortreatment group, and 2200 mm³ for control group).

Some of the above studies are carried out on additional compounds of thedisclosure. For example, it is found that for the Compound of Example26, the concentration of Compound at which 50% of AR-V7 and AR-FL isdegraded in 24 hours (DC₅₀), as determined by immunoblot, is less than50 nM and less than 500 nM, respectively. In cell proliferation assays,the Compounds of Examples 26, 34 and 35 at 10 μM reduces cell counts bysubstantially more than 50% after 4 days of treatment of 22Rv1-Enz^(R)cells, an effect substantially blocked by pre-treatment with MG-132 (5μM). Similar results are obtained for the Compound of Example 24. In thein vivo mouse tumor model described above, using 22Rv1-Enz^(R) tumors,the Compound of Example 26 substantially reduces tumor mass beginning ataround 3 weeks of treatment through 7 weeks of treatment at 8.3 mg/kgand 0.83 mg/kg (tumor mass at 7 weeks, control approx. 1500 mm³;treatment groups <600 mm³). No significant changes in animal body massobserved.

What is claimed is:
 1. A compound having a chemical structureARB-L-E3LB, wherein ARB is an AR binding moiety that does not bind to aligand binding domain, E3LB is an E3 ligase binding moiety, and L orLink is a linker coupling the AR binding moiety to the E3 ligase bindingmoiety.
 2. The compound of claim 1, wherein the AR binding moiety bindsto one more of AR splice variants V1 to V15, for example, to AR splicevariant V7 (AR-V7).
 3. The compound of claim 1, wherein the AR bindingmoiety is selected from:

wherein: A is 3-7 membered alicyclic with 0-4 heteroatoms (e.g.,morpholinyl) or aryl, heteroaryl independently substituted by 1 or morehalo, hydroxyl, nitro, CN, C≡CH, NR²R³, OCH₃, OC₁₋₃ alkyl (optionallysubstituted by 1 or more halo), CH₂F, CHF₂, CF₃, C₁₋₆ alkyl (linear,branched, optionally substituted by 1 or more halo, C₁₋₆ alkoxyl), C₁₋₆alkoxyl (linear, branched, optionally substituted by 1 or more halo),C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-6 membered alicyclic with 0-4 heteroatomsand substituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, CF₃, C₁₋₆alkyl (linear, branched, optionally substituted by 1 or more halo, C₁₋₆alkoxy), C₁₋₆ alkoxy (linear, branched, optionally substituted by 1 ormore halo), C₂₋₆ alkenyl, or C₂₋₆ alkynyl; B is aryl (e.g., phenyl),heteroaryl (e.g., imidazolyl) independently substituted by 1 or morehalo, hydroxyl, nitro, CN, C≡CH, NR²R³, OCH₃, OC₁₋₃ alkyl (optionallysubstituted by 1 or more halo), CF₃, C₁₋₆ alkyl (linear, branched,optionally substituted by 1 or more halo, C₁₋₆ alkoxyl), C₁₋₆ alkoxyl(linear, branched, optionally substituted by 1 or more halo), C₂₋₆alkenyl, C₂₋₆ alkynyl, 3-6 membered alicyclic with 0-4 heteroatoms andsubstituted by 1 or more halo, hydroxyl, nitro, CN, C≡CH, CF₃, C₁₋₆alkyl (linear, branched, optionally substituted by 1 or more halo, C₁₋₆alkoxy), C₁₋₆ alkoxy (linear, branched, optionally substituted by 1 ormore halo), C₂₋₆ alkenyl, or C₂₋₆ alkynyl, wherein the linker L isattached to B; and R¹ is each independently H, OH, CONH₂, CONR²R³,SONH₂, SONR²R³, SO₂NH₂, SO₂NR²R³, NHCO—C₁₋₃ alkyl (optionallysubstituted by 1 or more halo), NR²COC₁₋₃ alkyl (optionally substitutedby 1 or more halo), NR²SO₂C₁₋₃ alkyl (optionally substituted by 1 ormore halo), NR²SOC₁₋₃ alkyl (optionally substituted by 1 or more halo),CN, C═CH, NH₂, NR²R³, OCH₃, OC₁₋₃ alkyl (optionally substituted by 1 ormore halo), CHF₂, CH₂F, CF₃, halo, C₁₋₆ alkyl (linear, branched,optionally substituted by 1 or more halo, C₁₋₆ alkoxyl) or, ifapplicable, taken together with an R¹ on an adjacent bonded atom,together with the atoms they are attached to, form a 3-6 membered ringalicyclic, aryl, or heteroaryl system containing 0-2 heteroatoms, andR², R³ is independently H, halo, C₁₋₆ alkyl (optionally substituted by 1or more F) or taken together with the atom they are attached to, form a3-8 membered ring system containing 0-2 heteroatoms.
 4. The compound ofclaim 3, wherein A is:

wherein X is CH or N.
 5. The compound of claim 3, wherein B is:


6. The compound of claim 1, wherein the E3 ligase binding moietycomprises a structure selected from the group consisting of:

wherein “

” in the above structures, represents a bond that may be stereospecific((R) or (S)), or non-stereospecific, and wherein: R¹ is eachindependently H, OH, CONH₂, CONR²R³, SONH₂, SONR²R³, SO₂NH₂, SO₂NR²R³,NHCO—C₁₋₃ alkyl (optionally substituted by 1 or more halo), NR²COC₁₋₃alkyl (optionally substituted by 1 or more halo), NR²SO₂C₁₋₃ alkyl(optionally substituted by 1 or more halo), NR²SOC₁₋₃ alkyl (optionallysubstituted by 1 or more halo), CN, C═CH, NH₂, NR²R³, OCH₃, OC₁₋₃ alkyl(optionally substituted by 1 or more halo), CHF₂, CH₂F, CF₃, halo, C₁₋₆alkyl (linear, branched, optionally substituted by 1 or more halo, C₁₋₆alkoxyl) or, if applicable, taken together with an R¹ on an adjacentbonded atom, together with the atoms they are attached to, form a 3-6membered ring alicyclic, aryl, or heteroaryl system containing 0-2heteroatoms, and R², R³ are each independently H, halo, C₁₋₆ alkyl(optionally substituted by 1 or more F) or taken together with the atomthey are attached to, form a 3-8 membered ring system containing 0-2heteroatoms; and R⁴ is selected from H, alkyl (linear, branched,optionally substituted with R⁵), OH, R⁵OCOOR⁶, R⁵OCONR⁵R⁷,CH₂-heterocyclyl optionally substituted with R⁵, or benzyl optionallysubstituted with R⁵; R⁵ and R⁷ are each independently a bond, H, alkyl(linear, branched), cycloalkyl, aryl, hetaryl heterocyclyl, or —C(═O)R⁶each of which is optionally substitute; and R⁶ is selected from CONR⁵R⁷,OR⁵, NR⁵R⁷, SR⁵, SO₂R⁵, SO₂NR⁵R⁷, CR⁵R⁷, CR⁵NR⁵R⁷, aryl, hetaryl, alkyl(linear, branched, optionally substituted), cycloalkyl, heterocyclyl,P(O)(OR⁵)R⁷, P(O)R⁵R⁷, OP(O)(OR⁵)R⁷, OP(O)R⁵R⁷, Cl, F, Br, I, CF₃, CHF₂,CH₂F, CN, NR⁵SO₂NR⁵R⁷, NR⁵CONR⁵R⁷, CONR⁵COR⁷, NR⁵C(═N—CN)NR⁵R⁷,C(═N—CN)NR⁵R⁷, NR⁵C(—N═CN)R⁷, NR⁵C(═C—NO₂)NR⁵R⁷, SO₂NR⁵COR⁷, NO₂, CO₂R⁵,C(C═N—OR⁵)R⁷, CR⁵, CR⁵R⁷, CCR⁵, S(C═O)(C═N—R⁵)R⁷, SF₅, R⁵NR⁵R⁷,(R⁵O)_(n)R⁷, or OCF₃, where n is an integer from 1 to
 10. 7. Thecompound of claim 1, wherein the E3 ligase binding moiety comprises astructure selected from:

wherein in each moiety: R⁸ is H, a straight chain or branched C₁₋₈ alkyl(e.g., methyl, ethyl, isopropyl, tert-butyl), C₃₋₆ cycloalkyl (e.g.,cyclopropyl), halo, CFH₂, CF₂H, or CF₃; R⁹ is a H, halo,4-methylthiazol-5-ylm, or oxazol-5-yl; R¹⁰ are independently optionallysubstituted alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl),optionally substituted cycloalkyl (e.g., cyclopropyl), optionallysubstituted cycloalkylalkyl, optionally substituted arylalkyl,optionally substituted aryl, optionally substituted thioalkyl whereinthe substituents attached to the S atom of the thioalkyl are optionallysubstituted alkyl, optionally substituted branched alkyl, optionallysubstituted heterocyclyl, (CH₂)_(v)COR¹⁴, CH₂CHR¹⁵COR¹⁶ or CH₂R¹⁷, wherev=1 to 3; R¹⁴ and R¹⁶ are independently selected from OH, NR¹⁸R¹⁹, or—OR²⁰ (as defined hereinbelow); R¹⁵ is —NR¹⁸R¹⁹; R¹⁷ is optionallysubstituted aryl or optionally substituted heterocyclyl, where theoptional substituents include alkyl and halogen; R¹⁸ is hydrogen oroptionally substituted alkyl; R¹⁹ is hydrogen, optionally substitutedalkyl, optionally substituted branched alkyl, optionally substitutedarylalkyl, optionally substituted heterocyclyl, —CH₂(OCH₂CH₂O)_(n)CH₃,or a polyamine chain, where w=1 to 8; each R¹¹ is independentlyoptionally substituted alkyl (e.g., methyl, ethyl, isopropyl,tert-butyl), optionally substituted cycloalkyl (e.g., cyclopropyl),optionally substituted aryl, optionally substituted arylalkyl,optionally substituted arylalkoxy, optionally substituted heteroaryl,optionally substituted heterocyclyl, optionally substitutedheterocycloalkyl wherein the substituents are alkyl, halogen, or OH. 8.The compound of claim 1, wherein the E3 ligase binding moiety comprisesa structure selected from the group consisting of:

wherein: R¹⁰ and R¹¹ are each as defined in Compound 1.9; R¹² and R¹³are independently hydrogen, optionally substituted alkyl (e.g., methyl),or optionally substituted cycloalkyl; X is CH₂, NR², or O; Y is S or O;D is a bond (direct bond between X and L) or a ring which may be aryl orheteroaryl, independently substituted by 1 or more halo, hydroxyl,nitro, CN, C≡CH, NR²R³, OCH₃, OC₁₋₃ alkyl (optionally substituted by 1or more halo), CF₃, C₁₋₆ alkyl (linear, branched, optionally substitutedby 1 or more halo, C₁₋₆ alkoxyl), C₁₋₆ alkoxyl (linear, branched,optionally substituted by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl,3-6 membered alicyclic with 0-4 heteroatoms and substituted by 1 or morehalo, hydroxyl, nitro, CN, C≡CH, CF₃, C₁₋₆ alkyl (linear, branched,optionally substituted by 1 or more halo, C₁₋₆ alkoxy), C₁₋₆ alkoxy(linear, branched, optionally substituted by 1 or more halo), C₂₋₆alkenyl, or C₂₋₆ alkynyl; R², R³ are each independently H, halo, C₁₋₆alkyl (optionally substituted by 1 or more F) or taken together with theatom they are attached to, form a 3-8 membered ring system containing0-2 heteroatoms; and R²⁰ is selected from the group consisting of:

wherein A is a C₄₋₈ aliphatic ring, and B is an aryl (e.g., phenyl) orN-containing heteroaryl (e.g., pyridyl) and each is optionallysubstituted by alkyl or haloalkyl.
 9. The compound of claim 1, whereinthe E3 ligase binding moiety is:

wherein: R²² is aryl (e.g. phenyl) or heteroaryl (e.g., pyridyl)optionally substituted by halogen (e.g., F or Cl), e.g., mono-, di ortri-substituted independently by halogen; R²¹ is aryl (e.g. phenyl) orheteroaryl (e.g., pyridyl), optionally substituted by halogen (e.g., For Cl), e.g., mono-, di- or tri-substituted by halogen, CN, ethynyl,cyclopropyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy,other C₁₋₆ alkyl, other C₁₋₆ alkenyl and C₁₋₆ alkynyl; R²³ is selectedfrom alkyl (e.g., methyl, ethyl, isopropyl, propyl, n-butyl, sec-butyl,isobutyl, t-butyl, n-pentyl, t-pentyl, isoamyl, neopentyl, n-hexyl),substituted alkyl, alkenyl, substituted alkenyl, substituted alkynyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,substituted cycloalkyl, alkenyl and substituted cycloalkenyl; R²⁴ is H,alkyl (e.g., methyl), aryl, substituted alkyl, cycloalkyl, arylsubstituted cycloalkyl and alkoxy substituted cycloalkyl; and E ispara-substituted (1,4-disubstituted) aryl (e.g., phenyl), single ormultiple N containing heteroaryl (e.g., pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl), each optionally further substituted by —OCH₃, —OCH₂CH₃ andhalogen.
 10. The compound of claim 1, wherein the AR binding moiety is:


11. The compound of claim 1, wherein the E3 ligase binding moiety isselected from:

wherein the substituents are as defined herein.
 12. The compound ofclaim 1, wherein the E3 ligase binding moiety is selected from the groupconsisting of:


13. The compound of claim 1, wherein the linker group (“L”) is selectedfrom:

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein m is from 0-12;

Wherein m is from 0-12;

wherein m is from 0-12;

wherein m is from 2-4;

wherein m is from 0-12;

wherein m is from 0-10;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein m is from 0-10;

wherein m is from 0-10;

wherein m is from 0-10;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein m is from 1-12;

wherein m is from 1-12;

wherein m is from 1-12; and

wherein m is from 0-10.
 14. The compound of claim 1, wherein the ARbinding moiety is selected from:

and wherein the E3 ligase binding moiety is selected from the groupconsisting of

and wherein the linker group (“L”) is selected from:

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein m is from 0-12;

wherein m is from 0-12;

wherein m is from 0-12;

wherein m is from 2-4;

wherein m is from 0-12;

wherein m is from 0-10;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein m is from 0-10;

wherein m is from 0-10;

wherein m is from 0-10;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein m is from 1-12;

wherein m is from 1-12;

wherein m is from 1-12; and

wherein m is from 0-10.
 15. The compound of claim 1, wherein thecompound is effective in causing or promoting the degradation of theandrogen receptor (AR) in a cell, or of causing or promoting apoptosisin a cell, e.g., a cancer cell.
 16. A compound selected from the groupconsisting of:


17. A pharmaceutical composition comprising a compound of claim 1, and apharmaceutically acceptable carrier, additive and/or excipient.
 18. Amethod of treating a disease state or condition in a patient whereindysregulated protein activity is responsible for said disease orcondition, said method comprising administering an effective amount of acompound according to claim 1, to a patient in need thereof.
 19. Amethod of degrading an androgen receptor in a cell, e.g., a mutated ARsuch as any AR-V1 to AR-V15 splice variant, e.g., the AR-V7 splicevariant, said method comprising administering an effective amount of acompound according to claim 1, to such cell, e.g., a cancer cell.
 20. Amethod of inducing apoptosis in a cell, e.g., a cancer cell, said methodcomprising administering an effective amount of a compound according toclaim 1, to such cell.